Quinoline-4-carboxamide derivatives as NK-3 and NK-2 receptor antagonists

ABSTRACT

A compound, or a solvate or a salt thereof, of formula (I):                    
     wherein, Ar is an optionally substituted aryl or a C 5-7  cycloalkdienyl group, or an optionally substituted C 5-7  cycloalkyl group, or an optionally substituted single or fused ring aromatic heterocyclic group; 
     R is hydrogen, linear or branched C 1-6  alkyl, C 3-7  cycloalkyl, C 3-7  cycloalkylalkyl; 
     R 1  represents hydrogen or up to three optional substituents selected from the list consisting of: C 1-6  alkyl, C 1-6  alkenyl, aryl, C 1-6  alkoxy, hydroxy, halogen, nitro, cyano, carboxy, carboxamido, sulphonamido, C 1-6  alkoxycarbonyl, trifluoromethyl, acyloxy, amino or mono- and di-C 1-6  alkylamino, 
     R 2  represents a moiety —(CH 2 ) n —NYY 2  wherein n is an integer in the range of from 1 to 9, Y 1  and Y 2  are independently selected from C 1-6 -alkyl; C 1-6  alkyl substituted with hydroxy, alkoxy, C 1-6  alkylamino or bis (C 1-6  alkyl) amino; C3-6 cycloalkyl; C4-6 azacycloalkyl; C 1-6 -alkenyl; aryl or aryl-C 1-6 -alkyl or Y 1  and Y 2  together with the nitrogen atom to which they are attached represent an optionally substituted N-linked single or fused ring heterocyclic group; 
     R 3  is branched or linear C 1-6  alkyl, C 3-7  cycloalkyl, C 4-7  cycloalkylalkyl, optionally substituted aryl, or an optionally substituted single or fused ring aromatic heterocyclic group; and R 4  represents hydrogen or C 1-6  alkyl, R 5  represents hydrogen or halogen; a process for preparing such compounds, a pharmaceutical composition comprising such compounds and the use of such compounds and composition in medicine.

This is a continuation of application Ser. No. 10/159,218 filed May 31,2002, which is a continuation of Ser. No. 09/856,085, filed Sep. 4,2001, which is a 371 application of International Application No.PCT/EP99/09115, filed Nov. 19, 1999.

The present invention relates to novel compounds, in particular to novelquinoline derivatives, to processes for the preparation of suchcompounds, to pharmaceutical compositions containing such compounds andto the use of such compounds in medicine.

The mammalian peptide Neurokinin B (NKB) belongs to the Tachykinin (TK)peptide family which also include Substance P (SP) and Neurokinin A(NKA). Pharmacological and molecular biological evidence has shown theexistence of three subtypes of TK receptor (NK₁, NK₂ and NK₃) and NKBbinds preferentially to the NK₃ receptor although it also recognises theother two receptors with lower affinity (Maggi et al, 1993, J. Auton.Pharmacol., 13, 23-93).

Selective peptidic NK₃ receptor antagonists are known (Drapeau, 1990Regul. Pept., 31, 125-135), and findings with peptidic NK₃ receptoragonists suggest that NKB, by activating the NK₃ receptor, has a keyrole in the modulation of neural input in airways, skin, spinal cord andnigro-striatal pathways (Mycrs and Undem, 1993 J. Physiol., 470,665-679; Counture et al., 1993, Regul. Peptides, 46, 426-429, Mccarsonand Krause, 1994, J. Neurosci., 14 (2), 712-720; Arenas et al. 1991, J.Neurosci 18, 2332-8). However, the peptide-like nature of the knownantagonists makes them likely to be too labile from a metabolic point ofview to serve as practical therapeutic agents.

Copending International Patent Application number PCT/EP98/03014discloses certain compounds stated to be non-peptide NK-3 antagonistsand also to have NK-2 antagonist activity. These compounds are thereforeconsidered to be of potential use in the prevention and treatment of awide variety of clinical conditions which are characterized byoverstimulation of the tachykinin receptors, in particular NK-3 andNK-2.

We have now discovered a further novel class of non-peptide NK-3antagonists which are far more stable from a metabolic point of viewthan the known peptidic NK-3 receptor antagonists and are of potentialtherapeutic utility. These compounds also have NK-2 antagonist activityand are therefore considered to be of potential use in the preventionand treatment of a wide variety of clinical conditions which arecharacterized by overstimulation of the tachykinin receptors, inparticular NK-3 and NK-2.

These conditions include respiratory diseases, such as chronicobstructive pulmonary disease (COPD), asthma, airway hyperreactivity,cough; inflammatory diseases such as inflammatory bowel disease,psoriasis, fibrositis, osteoarthritis, rheumatoid arthritis andinflammatory pain; neurogenic inflammation or peripheral neuropathy,allergies such as eczema and rhinitis; ophthalmic diseases such asocular inflammation, conjunctivitis, vernal conjuctivitis and the like;cutaneous diseases, skin disorders and itch, such as cutaneous wheal andflare, contact dermatitis, atopic dermatitis, urticaria and othereczematoid dermatitis; adverse immunological reactions such as rejectionof transplanted tissues and disorders related to immune enhancement orsuppression such as systhemic lupus erythematosis; gastrointestinal (GI)disorders and diseases of the GI tract such as disorders associated withthe neuronal control of viscera such as ulcerative colitis, Crohn'sdisease, irritable bowel syndrome (IBS), gastro-exophageous reflexdisease (GERD); urinary incontinence and disorders of the bladderfunction; renal disorders (hereinafter referred to as the ‘PrimaryConditions’).

Certain of these compounds also show CNS activity and hence areconsidered to be of particular use in the treatment of disorders of thecentral nervous system such as anxiety, depression, psychosis andschizophrenia; neurodegenerative disorders such as AIDS relateddementia, senile dementia of the Alzheimer type, Alzheimer's disease,Down's syndrome, Huntington's disease, Parkinson's disease, movementdisorders and convulsive disorders (for example epilepsy); demyelinatingdiseases such as multiple sclerosis and amyotrophic lateral sclerosisand other neuropathological disorders such as diabetic neuropathy, AIDSrelated neuropathy, chemotherapy-induced neuropathy and neuralgia;addiction disorders such as alcoholism; stress related somaticdisorders; reflex sympathetic dystrophy such as shoulder/hand syndrome;dysthymic disorders; eating disorders (such as food intake disease);fibrosing and collagen diseases such as scleroderma and eosinophilicfascioliasis; disorders of the blood flow caused by vasodilation andvasospastic diseases such as angina, migraine and Reynaud's disease andpain or nociception, for example, that is attributable to or associatedwith any of the foregoing conditions especially the transmission of painin migraine, (hereinafter referred to as the ‘Secondary Conditions’).

The compounds of formula (I) are also considered to be useful asdiagnostic tools for assessing the degree to which neurokinin-3 andneurokinin-2 receptor activity (normal, overactivity or underactivity)is implicated in a patient's symptoms.

According to the present invention there is provided a compound, or asolvate or a salt thereof, of formula (I):

wherein, Ar is an optionally substituted aryl or a C₅₋₇ cycloalkdienylgroup, or an optionally substituted C₅₋₇ cycloalkyl group, or anoptionally substituted single or fused ring aromatic heterocyclic group;

R is hydrogen, linear or branched C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₇cycloalkylalkyl;

R₁ represents hydrogen or up to three optional substituents selectedfrom the list consisting of: C₁₋₆ alkyl, C₁₋₆ alkenyl, aryl, C₁₋₆alkoxy, hydroxy, halogen, nitro, cyano, carboxy, carboxamido,sulphonamido, C₁₋₆ alkoxycarbonyl, trifluoromethyl, acyloxy, amino ormono- and di-C₁₋₆ alkylamino;

R₂ represents a moiety —(CH₂)_(n)—NY₁Y₂ wherein n is an integer in therange of from 1 to 9, Y₁ and Y₂ are independently selected fromC₁₋₆-alkyl; C₁₋₆ alkyl substituted with hydroxy, alkoxy, C₁₋₆ alkylaminoor bis (C₁₋₆ alkyl) amino; C3-6 cycloalkyl; C4-6 azacycloalkyl;C₁₋₆-alkenyl; aryl or aryl-C₁₋₆-alkyl or Y₁ and Y₂ together with thenitrogen atom to which they are attached represent an optionallysubstituted N-linked single or fused ring heterocyclic group;

R₃ is branched or linear C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₄₋₇cycloalkylalkyl, optionally substituted aryl, or an optionallysubstituted single or fused ring aromatic heterocyclic group; and

R₄ represents hydrogen or C₁₋₆ alkyl.

R₅ represents hydrogen or halogen.

Preferably R₅ represents hydrogen. In another preferred aspect R5 ischloro or bromo.

Suitably, Ar represents optionally substituted phenyl,unsubstitutedphenyl or cyclohexyl.

Suitably, Ar represents cyclohexyl.

Preferably Ar is phenyl or cyclohexyl.

Suitably, R represents C₁₋₆ alkyl, for example methyl or ethyl oriso-propyl.

In one preferred aspect, R is ethyl. In another preferred aspect, R ismethyl or isopropyl.

Suitably R₁ represents hydrogen, C₁₋₆ alkoxy, for example methoxy, orhydroxy.

Preferably, R₁ represents hydrogen. In another preferred aspect, R1 ismethoxy or hydroxy.

Suitably, NY₁Y₂ represents an optionally substituted N-linked single orfused ring heterocyclic group.

Suitable N-linked single or fused heterocyclic groups, include groups inwhich any single or fused ring is saturated or unsaturated and consistsof 5- or 6-ring atoms, said ring atoms optionally comprising 1 or 2additional heteroatoms selected from O or N and wherein one or two ringatoms are optionally substituted with one or two oxo groups or one ortwo of hydroxy, carboxy, carboxy C1-6 alkyl, C₁₋₆ alkoxycarbonyl,aminocarbonyl, C1-6 alkylcarbonyl optionally substituted with anaromatic heterocyclic group, arylcarbonyl, aryl C1-6 alkylcarbonyl,carboxy C1-6 alklycarbonyl, carboxyarylcarbonyl, amino, C1-6alkylcarbonylamino, C₁₋₆ alkyl, C₁₋₆ hydroxyalkyl, aryl, aryl, C1-6alkyl, C₃₋₇ cycloalkyl, optionally substituted C4-7 cycloalkenyl,optionally substituted C4-7 azacycloalkyl, optionally substituted C4-7diazacycloalkyl, optionally substituted C4-7 oxaazacycloalkyl,optionally substituted C4-7 thiazacycloalkyl, optionally substitutedC4-7 thiazacycloalkenyl, C₃₋₇ cycloalkylalkyl, hydroxy C1-6 alkoxy C1-6alkyl, C1-6 alkoxy C1-6 alkyl, di C1-6 alkylaminocarbonyl, di C1-6alkylamino C1-6 alkylcarbonyl, optionally substituted C4-7 azacycloalkylC1-6 alkylcarbonyl, optionally substituted C4-7 diazacycloaklyl C1-6alkylcarbonyl, optionally substituted C4-7oxaazacycloalkyl C1-6alkylcarbonyl, optionally susbtituted carboxamidine, C1-6alkylaminothiocarbonyl, optionally substituted nitrovinyl,aminosulphonyl, di C1-6 alklyaminosulphonyl, or an optionallysubstituted spiroheterocyclic ring or a single or fused ring aromaticheterocyclic group, or the substituents on adjacent ring atoms form acarbocyclic ring; said aryl or aromatic heterocyclic groups beingoptionally substituted with one or two C₁₋₆ alkyl, alkoxy, hydroxy,halogen or halogenalkyl groups; wherein, unless otherwise definedoptionally substituted means substituted with up to three substituentsselected from the list consisting of: amino, alkylamino, alkyl, aryl,heterocyclyl, alkylaryl, aralkyl, oxo, hydroxy and nitrile.

Preferably, the additional heteroatom is N.

Favoured optional substituents for the N-linked single or fusedheterocyclic groups are selected from carboxy C1-6 alkyl, aminocarbonyl,C1-6 alkylcarbonyl optionally substituted with an aromatic heterocyclicgroup, arylcarbonyl, aryl C1-6 alkylcarbonyl, carboxy C1-6alklycarbonyl, carboxyarylcarbonyl, amino, C1-6 alkylcarbonylamino, C₁₋₆alkyl, C₁₋₆ hydroxyalkyl, aryl, aryl C1-6 alkyl, C₃₋₇ cycloalkyl,optionally substituted C4-7 cycloalkenyl, optionally substituted C4-7azacycloalkyl, optionally substituted C4-7 diazacycloalkyl, optionallysubstituted C4-7 oxaazacycloalkyl, optionally substituted C4-7thiazacycloalkyl, optionally substituted C4-7 thiazacycloalkenyl, C₃₋₇cycloalkylalkyl, hydroxy C1-6 alkoxy C1-6 alkyl, C1-6 alkoxy C1-6 alkyl,di C1-6 alkylaminocarbonyl, di C1-6 alkylamino C1-6 alkylcarbonyl,optionally substituted C4-7 azacycloalkyl C1-6 alkylcarbonyl, optionallysubstituted C4-7 diazacycloaklyl C1-6 alkylcarbonyl, optionallysubstituted C4-7oxaazacycloalkyl C1-6 alkylcarbonyl, optionallysusbtituted carboxamidine, C1-6 alkylaminothiocarbonyl, optionallysubstituted nitrovinyl, aminosulphonyl, di C1-6 alklyaminosulphonyl, oran optionally substituted spiroheterocyclic ring; wherein, unlessotherwise defined optionally substituted means substituted with up tothree substituents selected from the list consisting of: amino,alkylamino, alkyl, aryl, heterocyclyl, alkylaryl, aralkyl, oxo, hydroxy,nitrile. Preferred optional substituents for the N-linked single orfused heterocyclic groups include isopropylcarbonyl, hydroxyethyl,cyclohexyl, phenyl, benzyl, isopropyl, phenethyl, 1-piperidinyl,hydroxyethoxyethyl, (4-hydroxy)-1-piperidinyl, 4-piperidinyl,(1-methyl)-4-piperidinyl, dimethylaminomethylcarbonyl,diethylaminoethylcarbonyl, (4-methyl)-1-piperazinylmethylcarbonyl,4-morpholinylethylcarbonyl, amino, (4-methyl)-1-piperazinyl,1-piperazinyl, N-methyl-N′-cyanocarboxamidine, 2-thiazolinyl,pyrrolidinyl-N-cyanomethyleneimine, pyrrolidinyl-N-methylmethyleneimine,1-pyrrolidinyl-2-nitrovinyl, carboxamidine, carboxyethylcarbonyl,pyrrolidinyl-N-methylsulphonylmethyleneimine,(2-carboxy)-phenylcarbonyl, aminosulphonyl, dimethylaminosulphonyl,carboxymethyl.

When present oxo substituents are preferably alpha to the point oflinkage of the N-linked single or fused heterocyclic group.

When a hetero atom of the N-linked single or fused heterocyclic group issubstituted, preferred substituents are selected from C₁₋₆ alkyl,hydroxy C1-6 alkyl for example hydroxyethyl, C₃₋₇ cycloalkyl, C₃₋₇cycloalkylalkyl, aryl and arylalkyl, for example methyl, ethyl,isopropyl, phenyl,phenethyl, or benzyl, optionally substituted C4-7azacycloalkyl for example 4-piperidinyl or (1-methyl)-4-piperidinyl,dialkylaminoalkylcarbonyl for example dimethylaminomethylcarbonyl ordiethylaminoethylcarbonyl, hydroxy C1-6 alkoxy C1-6 alkyl for examplehydroxyethoxyethyl, optionally substituted C4-7 diazacycloalkyl C1-6alkylcarbonyl or C4-7 oxaazacycloalkyl C1-6 alkylcarbonyl for example,(4-methyl)-1-piperazinylmethylcarbonyl, 4-morpholinylethylcarbonyl,optionally substituted carboxamidine for example carboxamidine orN-methyl-N′-cyanocarboxamidine, or pyrrolidinyl-N-cyanomethyleneimine orpyrrolidinyl-N-methylmethyleneimine orpyrrolidinyl-N-methylsulphonylmethyleneimine, optionally substitutednitrovinyl for example 1-pyrrolidinyl-2-nitrovinyl, optionallysubstituted C4-7 thiazacycloalkenyl for example 2-thiazolinyl, carboxyC1-6 alklycarbonyl for example carboxyethylcarbonyl, carboxyarylcarbonylfor example (2-carboxy)-phenylcarbonyl, aminosulphonyl, di C1-6alklyaminosulphonyl for example dimethylaminosulphonyl, carboxy C1-6alkyl for example carboxymethyl.

Fused heterocyclic groups include groups having one or more rings whichshare one or more atoms, such as spiro fused rings, or one or morebonds.

A suitable N-linked single ring heterocyclic group comprising a5-membered saturated heterocyclic ring is a pyrrolidin-1-yl group.

A suitable N-linked single ring heterocyclic group comprising a6-membered saturated heterocyclic ring is an optionally substitutedpiperidin-1-yl group, for example a 4-(piperidin-1-yl)piperidin-1-ylgroup or 4-aminopiperidin-1-yl group.

A suitable N-linked single ring 6-membered saturated heterocyclic groupcomprising an additional heteroatom is an optionally substitutedpiperazin-1yl group, for example an optionally substituted4-alkylpiperazin-1-yl group.

A suitable N-linked fused ring heterocyclic group includes a 5-or6-membered saturated or unsaturated heterocyclic ring fused to a benzenering.

A suitable N-linked fused ring heterocyclic group comprising a6-membered saturated heterocyclic ring fused to a benzene ring is a2-(1,2,3,4-tetrahydro)isoquinolinyl group.

Suitable, N-linked fused heterocyclic groups include spiro fused groups,for example 1,4-dioxa-8-azaspiro[4.5]dec-8-yl group or3-oxo-2,8-diazaspiro[4.5]dec-8-yl or2,4-dioxo-1,3,8-triazaspiro[4.5]dec-8-yl or 2,7-diazaspiro[4.4]non-2-ylor 2,3-dioxa-1,8-diazaspiro[4.5]dec-8-yl.

One preferred value of —NY₁Y₂ is a piperazin-1-yl group, especially a4-hydroxyalkylpiperazin-1-yl, or4-(dialkylaminoalkylcarbonyl)piperazin-1-yl, or4-(azacycloalkyl)piperazin-1-yl, which piperazinyl group may besubstituted or unsubstituted

A particularly preferred value of —NY₁Y₂ is a group of formula (a), (b)(c) or (d):

wherein T₁ represents isopropylcarbonyl, hydroxyethyl, cyclohexyl,phenyl, benzyl, isopropyl, phenethyl, 1-piperidinyl, hydroxyethoxyethyl,(4-hydroxy)-1-piperidinyl, 4-piperidinyl, (1-methyl)-4-piperidinyl,dimethylaminomethylcarbonyl, diethylaminoethylcarbonyl,(4-methyl)-1-piperazinylmethylcarbonyl, 4-morpholinylethylcarbonyl,amino, (4-methyl)-1-piperazinyl, 1-piperazinyl,N-methyl-N′-cyanocarboxamidine, 2-thiazolinyl,pyrrolidinyl-N-cyanomethyleneimine, pyrrolidinyl-N-methylmethyleneimine,1-pyrrolidinyl-2-nitrovinyl, carboxamidine, carboxyethylcarbonyl,pyrrolidinyl-N-methylsulphonylmethyleneimine,(2-carboxy)-phenylcarbonyl, aminosulphonyl, dimethylaminosulphonyl,carboxymethyl.

wherein T₁ together with T₂ and the atoms to which each is attached forman optionally substituted single or fused ring heterocyclic group andeither T₃ together with T₄ form an optionally substituted single orfused ring heterocyclic group;

Suitably T₁ represents one of the following groups:

wherein R₆ represents H or a lower alkyl, preferably H or methyl, m isan integer from 1 to 5 and R₇ and R₈ represent a lower alkyl, preferablymethyl or ethyl or together form an heterocycle, for example apiperidine, morpholine or optionally substituted piperazine.

Q₁ represents 2-phthalic acid, a saturated or unsaturated C1-6carboxylic acid or an heterocycle for example 2-imidazolyl or thiazolyl.

In a group of formula (a), suitably T₁ represents also an heterocyclefor example imidazolyl, thiazolyl, pyridyl, pyrimidyl, tetrazolyl or T₁represents an optionally substituted carboxamidine or a correspondingquaternary carboxamidine derivative.

In a group of formula (a) suitable T₁ represents also one of thechemical entities below:

wherein R₉ and R₁₀ represent hydrogen, alkyl or together form a 5 to 7membered ring with the N atom to which they are attached, preferably apyrrolidin or piperidin ring and R₁₁ represents C₁₋₆ linear or branchedalkyl or optionally substituted aryl

wherein Q₂ is hydrogen, alkyl, aralkyl, aryl, cyano.

In a group of formula (a) suitable T1 represents also a sulphonamide offormula:

SO₂NR₁₂R₁₃

wherein R₁₂ and R₁₃ are independently selected from hydrogen; C₁₋₆alkyl; optionally substituted aryl or R₁₂ and R₁₃ together with thenitrogen atom to which they are attached represent an optionallysubstituted N-linked single or fused ring heterocyclic group.

In one particular aspect —NY₁Y₂ is a moiety of formula (a).

In one particular aspect —NY₁Y₂ is a moiety of formula (b).

In one particular aspect —NY₁Y₂ is a moiety of formula (c).

In one particular aspect —NY₁Y₂ is a moiety of formula (d).

Suitably, R₃ is optionally substituted aryl, preferably an unsubstitutedaryl group such as a phenyl group.

Suitably, R₄ is hydrogen.

Suitably, n is an integer from 1 to 6, favourably 1 to 4 and mostpreferably 1, 2 or 3.

Favourably, n′ represents 1.

Favourably, n′ represents 2.

Favourably, n′ represents 3.

Preferred compounds of formula (I) are those wherein: Ar is phenyl orcyclohexyl, R is methyl, ethyl, or isopropyl, R₁ is hydrogen or methoxyor hydroxy, R₂ is a moiety (CH₂)_(n) wherein n is 1, 2, 3 or 4, R₃ isphenyl and R₄ is hydrogen and NY₁Y₂ is:

(i) an optionally substituted piperazinyl group, especially a moiety ofthe above defined formula (a);

(ii) a moiety of the above defined formula (b); or

(iii) a moiety of the above defined formula (c); or

(iv) a moiety of the above defined formula (d). Further preferredcompounds of formula (I) are those wherein: Ar is phenyl or cyclohexyl,R is methyl, ethyl or isopropyl, R₁ is hydrogen, methoxy or hydroxy R₂is a moiety —(CH₂)_(n)—NY₁Y₂ wherein n is 1,R₃ is phenyl and R₄ ishydrogen and NY₁Y₂ is:

(i) an optionally substituted piperazinyl group, especially a moiety ofthe above defined formula (a); or

(ii) a moiety of the above defined formula (b).

In particular should be mentioned the compounds of examples 20, 29, 32,33, 34, 46, 47, 48, 53, 55, 62, 67, 78, 79, 80, 81 and 95.

The compounds of formula (I) may have at least one asymmetric centre—forexample the carbon atom labelled with an asterisk (*) in the compound offormula (I)—and therefore may exist in more than one stereoisomericform. The invention extends to all such stereoisomeric forms and tomixtures thereof, including racemates. In particular, the inventionincludes compounds wherein the asterisked carbon atom in formula (I) hasthe stereochemistry shown in formula (Ia):

wherein Ar, R, R₁, R₂, R₃, R₄ and R₅ are as defined in relation toformula (I).

The compounds of formula (I) or their salts or solvates are preferablyin pharmaceutically acceptable or substantially pure form. Bypharmaceutically acceptable form is meant, inter alia, having apharmaceutically acceptable level of purity excluding normalpharmaceutical additives such as diluents and carriers, and including nomaterial considered toxic at normal dosage levels.

A substantially pure form will generally contain at least 50% (excludingnormal pharmaceutical additives), preferably 75%, more preferably 90%and still more preferably 95% of the compound of formula (I) or its saltor solvate.

One preferred pharmaceutically acceptable form is the crystalline form,including such form in pharmaceutical composition. In the case of saltsand solvates the additional ionic and solvent moieties must also benon-toxic.

Suitable salts are pharmaceutically acceptable salts.

Suitable pharmaceutically acceptable salts include the acid additionsalts with the conventional pharmaceutical acids, for example maleic,hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic,citric, lactic, mandelic, tartaric, succinic, benzoic, ascorbic andmethanesulphonic.

Suitable pharmaceutically acceptable salts include salts of acidicmoieties of the compounds of formula (I) when they are present, forexample salts of carboxy groups or phenolic hydroxy groups.

Suitable salts of acidic moieties include metal salts, such as forexample aluminium, alkali metal salts such as lithium, sodium orpotassium, alkaline earth metal salts such as calcium or magnesium andammonium or substituted ammonium salts, for example those with loweralkylamines such as triethylamine, hydroxy alkylamines such as2-hydroxyethylamine, bis-(2-hydroxyethyl)-amine ortri-(2-hydroxyethyl)amine, cycloalkylamines such as bicyclohexylamine,or with procaine, dibenzylpiperidine, N-benzyl-β-phenethylamine,dehydroabietylamine, N,N′-bisdehydroabietylamine, glucamine,N-methylglucamine or bases of the pyridine type such as pyridine,collidine, quinine or quinoline.

Suitable solvates are pharmaceutically acceptable solvates.

Suitable pharmaceutically acceptable solvates include hydrates.

The term ‘alkyl’ (unless specified to the contrary) when used alone orwhen forming part of other groups (such as the ‘alkoxy’ group) includesstraight- or branched-chain alkyl groups containing 1 to 12 carbonatoms, suitably 1 to 6 carbon atoms, examples include methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl group.

The term ‘carbocylic’ refers to cycloalkyl and aryl rings.

The term ‘cycloalkyl’ includes groups having 3 to 12, suitably 4 to 6ring carbon atoms.

The term ‘aryl’ includes phenyl and naphthyl, preferably phenyl whichunless specified to the contrary optionally comprise up to five,preferably up to three substituents selected from halogen, alkyl,phenyl, alkoxy, haloalkyl, hydroxyalkyl, hydroxy, amino, nitro, cyano,carboxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkylcarbonyloxy, oralkylcarbonyl groups.

The term ‘aromatic heterocyclic group’ includes groups comprisingaromatic heterocyclic rings containing from 5 to 12 ring atoms, suitably5 or 6, and comprising up to four hetero-atoms in the or each ringselected from S, O or N.

Unless specified to the contrary, suitable substituents for anyheterocyclic group includes up to 4 substituents selected from the groupconsisting of: alkyl, alkoxy, aryl and halogen or any two substituentson adjacent carbon atoms, together with the carbon atoms to which theyare attached, may form an aryl group, preferably a benzene ring, andwherein the carbon atoms of the aryl group represented by the said twosubstituents may themselves be substituted or unsubstituted.

When used herein the term “halogen” refers to fluorine, chlorine,bromine and iodine, preferably fluorine, chlorine or bromine.

When used herein the term “acyl” includes residues of acids, inparticular a residue of a carboxylic acid such as an alkyl- oraryl-carbonyl group.

The invention also provides a process for the preparation of a compoundof formula (I), or a salt thereof and/or a solvate thereof, whichprocess comprises reacting a compound of formula (II) or an activederivative thereof:

wherein R′₁, R′₂, R′₃ and R′₅ are R₁, R₂, R₃ and R₅ respectively asdefined in relation to formula (I) or a group convertible to R₁, R₂, R₃and R₅ respectively; with a compound of formula (III):

wherein R′, R₄′ and Ar′ are R, R₄ and Ar as defined for formula (I) or agroup or atom convertible to R, R₄ and Ar respectively; to form acompound of formula (Ib):

wherein Ar′, R′, R′₁, R′₂, R′₃, R′₄ and R′₅ are as defined above, andthereafter carrying out one or more of the following optional steps:

(i) converting any one of Ar′, R′, R′₁, R′₂, R′₃, R′₄ and R′₅ to Ar, R,R₁, R₂, R₃, R₄ or R₅ respectively as required, to obtain a compound offormula (I);

(ii) converting a compound of formula (I) into another compound offormula (I); and

(iii) preparing a salt of the compound of formula (I) and/or a solvatethereof.

Suitable groups convertible into other groups include protected forms ofsaid groups.

Suitably Ar′, R′, R′₁, R′₂, R′₃, R′₄ or R′₅ each represents Ar, R, R₁,R₂, R₃, R₄ or R₅ respectively or a protected form thereof.

It is favoured if the compound of formula (II) is present as an activederivative.

A suitable active derivative of a compound of formula (II) is atransient activated form of the compound of formula (II) or a derivativewherein the carboxy group of the compound of formula (II) has beenreplaced by a different group or atom, for example by an acyl halide,preferably a chloride, or an acylazide or a carboxylic acid anhydride.

Other suitable active derivatives include: a mixed anhydride formedbetween the carboxyl moiety of the compound of formula (II) and an alkylchloroformate; an activated ester, such as a cyanomethyl ester,thiophenyl ester, p-nitrophenyl ester, p-nitrothiophenyl ester,2,4,6-trichlorophenyl ester, pentachlorophenyl ester, pentafluorophenylester, N-hydroxy-phtalimido ester, N-hydroxypiperidine ester,N-hydroxysuccinimide ester, N-hydroxy benzotriazole ester;alternatively, the carboxy group of the compound of formula (II) may beactivated using a carbodiimide or N,N′-carbonyldiimidazole.

The reaction between the compound of formula (II) or the activederivative thereof and the compound of formula (III) is carried outunder the appropriate conventional conditions for the particularcompounds chosen. Generally, when the compound of formula (II) ispresent as an active derivative the reaction is carried out using thesame solvent and conditions as used to prepare the active derivative,preferably the active derivative is prepared in situ prior to formingthe compound of formula (Ib) and thereafter the compound of formula (I)or a salt thereof and/or a solvate thereof is prepared.

For example, the reaction between an active derivative of the compoundof formula (II) and the compound of formula (III) may be carried out:

(a) by first preparing an acid chloride and then coupling said chloridewith the compound of formula (III) in the presence of an inorganic ororganic base in a suitable aprotic solvent such as dimethylformamide(DMF) at a temperature in a range from −70 to 50° C. (preferably in arange from −10 to 20° C.); or

(b) by treating the compound of formula (II) with a compound of formula(III) in the presence of a suitable condensing agent, such as forexample N,N′-carbonyl diimidazole (CDI) or a carbodiimide such asdicyclohexylcarbodiimide (DCC) orN-dimethylaminopropyl-N′-ethylcarbodiimide, preferably in the presenceof N-hydroxybenzotriazole (HOBT) to maximise yields and avoidracemization processes (see Synthesis, 453, 1972), orO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluroniumnhexafluorophosphate(HBTU), in an aprotic solvent, such as a mixture of acetonitrile (MeCN)and tetrahydrofuran (THF), for example a mixture in a volume ratio offrom 1:9 to 7:3 (MeCN:THF), at any temperature providing a suitable rateof formation of the required product, such as a temperature in the rangeof from −70 to 50° C., preferably in a range of from −10 to 25° C., forexample at 0° C.

A preferred reaction is set out in Scheme 1 shown below:

wherein Ar′, R′, R′₁, R′₂, R′₃, R′₄ and R′₅ are as defined above.

It will be appreciated that a compound of formula (Ib) may be convertedto a compound of formula (I), or one compound of formula (I) may beconverted to another compound of formula (I) by interconversion ofsuitable substituents. Thus, certain compounds of formula (I) and (Ib)are useful intermediates in forming other compounds of the presentinvention.

Accordingly, in a further aspect the invention provides a process forpreparing a compound of formula (I), or a salt thereof and/or a solvatethereof, which process comprises converting a compound of the abovedefined formula (Ib) wherein at least one of Ar′, R′, R′₁, R′₂, R′₃, R′₄or R′₅ is not Ar, R, R₁, R₂, R₃, R₄ or R₅ respectively, thereby toprovide a compound of formula (I); and thereafter, as required, carryingout one or more of the following optional steps:

(i) converting a compound of formula (I) into another compound offormula (I); and

(ii) preparing a salt of the compound of formula (I) and/or a solvatethereof.

Suitably, in the compound of formula (Ib) the variables Ar′, R′, R′₁,R′₂, R′₃, R′₄ and R′₅ are Ar, R, R₁, R₂, R₃, R₄ or R₅ respectively orthey are protected forms thereof.

The above mentioned conversions, protections and deprotections arecarried out using the appropriate conventional reagents and conditionsand are further discussed below.

A compound of formula (II) or the corresponding alkyl (such as methyl orethyl) ester wherein n is an integer 1, is prepared by reacting acompound of formula (IV) or the corresponding alkyl (such as methyl orethyl) ester:

wherein R′₁, R′₃ and R′₅ are as defined above and L₁ represents ahalogen atom such as a bromine atom, with a compound of formula (V):

HNY′₁Y′₂  (V)

wherein Y′₁ and Y′₂ are respectively Y₁ and Y₂ as defined in relation toformula (I) or protected forms thereof.

Suitably, Y′₁ and Y′₂ are Y₁ and Y₂.

Suitably, reaction between the compounds of formulae (IV) or thecorresponding alkyl (such as methyl or ethyl) ester and (V) is carriedout under conventional amination conditions, for example when L₁ is abromine atom then the reaction is conveniently carried out in an aproticsolvent, such as tetrahydrofuran or dimethylformamide at any temperatureproviding a suitable rate of formation of the required product, usuallyat ambient temperature; preferably the reaction is carried out in thepresence of triethylamine (TEA) or K₂CO₃.

A compound of formula (IV) or the corresponding alkyl (such as methyl orethyl) ester is prepared by appropriate halogenation of a compound offormula (VI) or the corresponding alkyl (such as methyl or ethyl) ester:

wherein R′₁, R′₃ and R′5 are as defined above in relation to formula(II).

Suitable halogenation reagents are conventional reagents depending uponthe nature of the halogen atom required, for example when L₁ is brominea preferred halogenation reagent is N-bromosuccinimide (NBS).

The halogenation of the compound of formula (VI) or the correspondingalkyl (such as methyl or ethyl) ester is carried out under conventionalconditions, for example bromination is carried out by treatment with NBSin an inert solvent, such as 1,2-dichloroethane or CH₃CN, at anytemperature providing a suitable rate of formation of the requiredproduct, suitably at an elevated temperature such as a temperature inthe range of 60° C. to 100° C., for example 80° C.; preferably thereaction is carried out in the presence of a catalytic amount on benzoylperoxide.

In the case in which the corresponding alkyl (such as methyl or ethyl)ester of compounds (VI), (IV) and (II) are utilised, an hydrolysis tocompound (II) is required before conversion to compound (Ib) inScheme 1. Such hydrolysis can be carried out under acidic conditions,such 10-36% hydrochloric acid at a temperature in the range between 30and 100° C. A compound of formula (II) wherein R′₂ represents—(CH₂)₂₋₉—NY₁Y₂, is conveniently prepared by reacting a compound offormula (VII):

wherein R′₁ and R′5 are as defined in relation to formula (II), with acompound of formula (VIII):

R₃′—CO—CH₂—(CH₂)p—T₅  (VIII)

wherein R′₃ is as defined in relation to formula (II), and T₅ is a group—NY₁Y₂ as defined in relation to formula (I) or a protected form thereofor a group convertible thereto, and p is an integer in the range of 2 to9; and thereafter as required removing any protecting group and/orconverting any group T₅ to NY₁Y₂.

The reaction between the compounds of formula (VII) and (VIII) isconveniently carried out using Pfitzinger reaction conditions (see forexample J. Prakt. Chem. 33, 100 (1886), J. Prakt. Chem. 38, 582 (1888),J. Chem. Soc. 106 (1948) and Chem. Rev. 35, 152 (1944)), for example inan alkanolic solvent such as ethanol, at any temperature providing asuitable rate of formation of the required product, but generally at anelevated temperature, such as the reflux temperature of the solvent, andpreferably in the presence of a base such as potassium hydroxide orpotassium tert-butoxide.

Protected forms of —NY₁Y₂ will vary according to the particular natureof the group being protected but will be chosen in accordance withnormal chemical practice.

Groups convertible to —NY₁Y₂ include groups dictated by conventionalchemical practice to be required and to be appropriate, depending uponthe specific nature of the —NY₁Y₂ consideration.

Suitable deprotection methods for deprotecting protected forms of NY₁Y₂and conversion methods for converting T₅ to NY₁Y₂ will be those usedconventionally in the art depending upon the particular groups underconsideration with reference to standard texts such as Greene, T. W. andWuts, P. G. M. Protective Groups in Organic Synthesis, John Wiley & SonsInc. New York, 1991 (Second Edt.) or in Kocienski, P. J. Protectinggroups. George Thieme Verlag, New York, 1994 and Chemistry of the AminoGroup, Patais (Ed.), Interscience, New York 1968; or Advanced OrganicChemistry, March J, John Wiley & Sons, New York, 1992.

A compound of formula (VIII) is prepared from a compound of formula(IX):

R₃′—CO—CH₂—(CH₂)_(p)—OH  (IX)

wherein R′₃ is as defined in relation to formula (II) and p is asdefined in relation to formula (VIII), by first halogenating, preferablybrominating, or mesylating the compound of formula (IX) and thereafterreacting the halogenation or mesylation product so formed with acompound capable of forming a group T₅ so as to provide the requiredcomound of formula (VII).

When T₅ is a group —NY₁Y₂, a compound capable of forming a group T₅, isa compound of the above defined formula (V).

The halogenation of the compound of formula (IX) is suitably carried outusing a conventional halogenation reagent. Mesylation is convenientlycarried out using mesyl chloride in an inert solvent such as methylenedichloride, at a temperature below room temperature, such as 0° C.,preferably in the presence of triethylamine. The reaction conditionsbetween the compound of formula (IX) and the compound capable of forminga group T₅ will be those conventional conditions dictated by thespecific nature of the reactants, for example when the T₅ required is agroup NY₁Y₂ and the required compound capable of forming a group T₅ is acompound of the above defined formula (V), then the reaction between thehalogenation or mesylation product of the compound of formula (IX) andthe compound of formula (V) is carried out under analogous conditions tothose described for the reaction between the compounds of formulae (IV)and (V).

Other compounds capable of forming a group T₅ will depend upon theparticular nature of T₅, but will be those appropriate compoundsdictated by conventional chemical practice with reference to standardtexts such as Chemistry of the Amino Group, Patais (Ed.), Interscience,New York 1968; and Advanced Organic Chemistry, March J, John Wiley &Sons, New York, 1992.

A compound of formula (IX) may be prepared by reacting a compound offormula (X):

wherein p is as defined in relation to formula (VIII), with a lithiumsalt of formula (XI):

R′₃Li  (XI)

wherein R′₃ is as defined in relation to formula (II).

The reaction between the compounds of formulae (X) and (XI) can becarried out in an aprotic solvent, such as diethyl-ether at anytemperature providing a suitable rate of formation of the requiredproduct, usually at a low temperature such as in the range of −10° C. to−30° C., for example −20° C.

The compounds of formula (III) are known commercially availablecompounds or they can be prepared from known compounds by known methods,or methods analogous to those used to prepare known compounds, forexample the methods described in Liebigs Ann. der Chemie, (1936), 523,199.

Chiral compound of formula (III) wherein Ar is a C₅ or C₇ cycloalkylgroup, R is methyl and R₄ is H are described in J. Org. Chem. (1996), 61(12), 4130-4135. A chiral compound of formula (III) wherein Ar isphenyl, R is isopropyl and R₄ is H is a known compound described in forexample Tetrahedron Lett. (1994), 35(22), 3745-6.

The compounds of formula (V) are known, commercially available compoundsor they can be prepared using methods analogous to those used to prepareknown compounds; for example the methods described in the Chemistry ofthe Amino Group, Patais (Ed.), Interscience, New York 1968; AdvancedOrganic Chemistry, March J, John Wiley & Sons, New York, 1992 ; J.Heterocyclic Chem. (1990), 27, 1559; Synthesis (1975), 135, Bioorg. Med.Chem. Lett. (1997), 7, 555, or Protective Groups in Organic Synthesis(second edition), Wiley Interscience, (1991) or other methods mentionedherein.

4-amino substituted piperidines are generally prepared by reductiveamination of 4oxo-piperidine, or a 4-oxo-piperidine N-substituted withan appropriated protecting group, with an appropriate amine. Typicalexamples can be found in J. Org. Chem. (1990), 55 (8), 2552-4 or ibid.(1995), 60 (15), 4928-9.

Certain diazaspirononane intermediates used herein are known compounds,for example that used to prepare example 68 is described in J. Med.Chem. (1990), 33 (8), 2270-2275.

The condensation of succinic and phthalic anhydrides used to generateexamples 83 and 85-87 is described in J. Indian Chem. Soc. (1979), 56(2), 171-2. 4-Heterocyclic substituted piperidine as used for thepreparation of example 77 are described in U.S. Pat. Nos. 4,329,348A19,820,511.

The compounds of formula (VII) are known compounds or they are preparedaccording to methods used to prepare known compounds for example thosedisclosed in J. Org. Chem. 21, 171 (1955); J. Org. Chem. 21, 169 (1955).

The compounds of formula (X) and (XI) are known compounds or they areprepared according to methods used to prepare known compounds forexample those disclosed by Krow G. R. in Organic Reactions, Vol 43, page251, John Wiley & Sons Inc. 1994 (for the compounds of formula (X)) andOrganometallics in Synthesis, Schlosser M.(Ed), John Wiley & Sons Inc.1994 (for the compounds of formula (XI)).

Compounds of formula (I) wherein R₂ represents a moiety —CH₂)_(n)—NY₁Y₂and —NY₁Y₂ is a piperazinyl group of formula (a) can suitably beprepared by reacting a compound of formula XII

wherein Ar′, R′, R′₁, R′₂, R′₃, R′₄ and R′₅ are as defined above, withreactive species of formula (XIII), for example:

wherein L₂ and L′₂ represent leaving groups such as —SAlkyl or —OAlkyl,preferably —SCH₃ and —OButyl and R₁₁ is as defined above.

Mono substitution of compounds of formula (XIII) by a compound offormula (XII) generates news structures bearing still one leaving group,L′₂, which can then be reacted with compounds of formula:

HNR₉R₁₀

wherein R₉ and R₁₀ are as defined above to give the final compounds offormula (I).

Substituted carboxamidinopiperazines are best prepared by reactingcompounds of formula (XII) with substituted isothiocyanates followingscheme 2

wherein R₁₂ represents lower alkyl, optionally substituted aryl oraralkyl, followed by the substitution of the group —SCH3, which takesplace of the leaving group L₂, with a compound of formula

HNR₉R₁₀

as mentioned above.

Unsubstituted carboxamidinopiperazines of formula (XVI)

are prepared by reacting a compound of formula (XII) with thebenzotriazole derivative of formula (XVII).

(Dimethylaminolethylene)dimethylammonium piperazines of formula (XVIII)

are prepared by heating a compound of formula (XII) with HBTU in thepresence of a base, for example TEA, in an appropriate solvent, usuallyone, or a mixture, of those used in peptide coupling reactions.Compounds of formula (I) wherein R₂ represents a moiety —(CH₂)_(n)—NY₁Y₂and —NY₁Y₂ is a piperazinyl group of formula (a) wherein T1 representscarboxy, alkoxycarbonyl, optionally substituted alkyl, optionallysubstituted aryl, aralkyl, cycloalkyl, can suitably be prepared byreacting a compound of formula XII with a compound of formula

T₁L₃

Wherein T₁ represents one of the radicals defined as above and L3 aleaving group for example halogen or sulfonate, preferably chlorine,bromine or mesylate. Compounds of formula (XII) are prepared by removingthe protective group of a compound of formula (XIX)

wherein Ar′, R′, R′₁, R′₂, R′₃, R′₄ and R′₅ are as defined above and Pis an amine protective group, for example fmoc or benzyl, preferablyfmoc. The protective group is removed by standard methods described inthe literature, for example the fmoc residue is splitted by action ofpiperidine at room temperature in a solvent like acetonitrile. Ashereinbefore mentioned, the compounds of formula (I) may exist in morethan one stereoisomeric form—and the process of the invention mayproduce racemates as well as enantiomerically pure forms. Accordingly, apure enantiomer of a compound of formula (I) is obtained by reacting acompound of the above defined formula (II) with an appropriateenantiomerically pure primary amine of formula (IIIa) or (IIIc):

wherein R′, R′₄ and Ar′ are as defined above, to obtain a compound offormula (I′a) or (I′c):

wherein Ar′, R′, R′₁, R′₂, R′₃, R′₄ and R′₅ are as defined above.

Compounds of formula (I′a) or (I′c) may subsequently be converted tocompounds of formula (Ia) or (Ic) by the methods of conversion mentionedbefore:

wherein Ar, R, R₁ R₂, R₃, R₄ and R₅ are as defined above.

Suitably, in the above mentioned compounds of formulae (Ia), (Ic),(I′a), (I′c), (IIIa) and (IIIc) R₄ represents hydrogen.

An alternative method for separating optical isomers is to useconventional, fractional separation methods in particular fractionalcrystallization methods. Thus, a pure enantiomer of a compound offormula (I) is obtained by fractional crystallisation of adiastereomeric salt formed by reaction of the racemic compound offormula (I) with an optically active strong acid resolving agent, suchas camphosulphonic acid, in an appropriate alcoholic solvent, such asethanol or methanol, or in a ketonic solvent, such as acetone. The saltformation process should be conducted at a temperature between 20° C.and 80° C., preferably at 50° C.

In the case in which other basic functionalities, such as primary,secondary or tertiary amine, are present in the molecule, a wider rangeof optically active acid resolving agents become available, includingtartaric acid, O,O′-di-p-toluoyltartaric acid and mandelic acid.

A suitable conversion of one compound of formula (I) into a furthercompound of formula (I) involves converting one group R₂ into anothergroup R₂ by for example:

(i) converting a ketal into a ketone, by such as mild acidic hydrolysis,using for example dilute hydrochloric acid;

(ii) reducing a ketone to a hydroxyl group by use of a borohydridereducing agent;

(iii) converting a carboxylic ester group into a carboxyl group usingbasic hydrolysis; and/or

(iv) reducing a carboxylic ester group to a hydroxymethyl group, by useof a borohydride reducing agent.

As indicated above, where necessary, the conversion of any group Ar′,R′, R′₁ R′₂, R′₃, R′₄ and R′₅ into Ar, R, R₁, R₂, R₃, R₄ or R₅ which asstated above are usually protected forms of Ar, R, R₁, R₂, R₃, R₄ or R₅may be carried out using appropriate conventional conditions such as theappropriate deprotection procedure.

It will be appreciated that in any of the above mentioned reactions anyreactive group in the substrate molecule may be protected anddeprotected according to conventional chemical practice, for example asdescribed by Greene, T. W. and Wuts, P.G.M. Protective Groups in OrganicSynthesis, John Wiley & Sons Inc. New York, 1991 (Second Edt.) or inKocienski, P. J. Protecting groups. George Thieme Verlag, New York,1994.

Suitable protecting groups in any of the above mentioned reactions arethose used conventionally in the art. Thus, for example suitablehydroxyl protecting groups include benzyl or trialkylsilyl groups.

The methods of formation and removal of such protecting groups are thoseconventional methods appropriate to the molecule being protected. Thusfor example a benzyloxy group may be prepared by treatment of theappropriate compound with a benzyl halide, such as benzyl bromide, andthereafter, if required, the benzyl group may be conveniently removedusing catalytic hydrogenation or a mild ether cleavage reagent such astrimethylsilyl iodide or boron tribromide.

As indicated above, the compounds of formula (I) have usefulpharmaceutical properties.

Accordingly the present invention also provides a compound of formula(I), or a pharmaceutically acceptable salt or solvate thereof, for useas an active therapeutic substance.

In particular, the present invention also provides a compound of formula(I), or a pharmaceutically acceptable salt or solvate thereof, for thetreatment or prophylaxis of the Primary and Secondary Conditions.

The present invention further provides a pharmaceutical compositioncomprising a compound of formula (I), or a pharmaceutically acceptablesalt or solvate thereof, and a pharmaceutically acceptable carrier.

The present invention also provides the use of a compound of formula(I), or a pharmaceutically acceptable salt or solvate thereof, in themanufacture of a medicament for the treatment of the Primary andSecondary Conditions.

As mentioned above the Primary conditions include respiratory diseases,such as chronic obstructive pulmonary disease (COPD), asthma, airwayhyperreactivity, cough; inflammatory diseases such as inflammatory boweldisease, psoriasis, fibrositis, osteoarthritis, rheumatoid arthritis andinflammatory pain; neurogenic inflammation or peripheral neuropathy,allergies such as eczema and rhinitis; ophthalmic diseases such asocular inflammation, conjunctivitis, vernal conjuctivitis and the like;cutaneous diseases, skin disorders and itch, such as cutaneous wheal andflare, contact dermatitis, atopic dermatitis, urticaria and othereczematoid dermatitis; adverse immunological reactions such as rejectionof transplanted tissues and disorders related to immune enhancement orsuppression such as systhemic lupus erythematosis; gastrointestinal (GI)disorders and diseases of the GI tract such as disorders associated withthe neuronal control of viscera such as ulcerative colitis, Crohn'sdisease, irritable bowel syndrome (IBS), gastro-exophageous reflexdisease (GERD); urinary incontinence and disorders of the bladderfunction; renal disorders.

As mentioned above, the Secondary conditions include disorders of thecentral nervous system such as anxiety, depression, psychosis andschizophrenia; neurodegenerative disorders such as AIDS relateddementia, senile dementia of the Alzheimer type, Alzheimer's disease,Down's syndrome, Huntington's disease, Parkinson's disease, movementdisorders and convulsive disorders (for example epilepsy); demyelinatingdiseases such as multiple sclerosis and amyotrophic lateral sclerosisand other neuropathological disorders such as diabetic neuropathy, AIDSrelated neuropathy, chemotherapy-induced neuropathy and neuralgia;addiction disorders such as alcoholism; stress related somaticdisorders; reflex sympathetic dystrophy such as shoulder/hand syndrome;dysthymic disorders; eating disorders (such as food intake disease);fibrosing and collagen diseases such as scleroderma and eosinophilicfascioliasis; disorders of the blood flow caused by vasodilation andvasospastic diseases such as angina, migraine and Reynaud's disease andpain or nociception, for example, that is attributable to or associatedwith any of the foregoing conditions especially the transmission of painin migraine.

Such a medicament, and a composition of this invention, may be preparedby admixture of a compound of the invention with an appropriate carrier.It may contain a diluent, binder, filler, disintegrant, flavouringagent, colouring agent, lubricant or preservative in conventionalmanner.

These conventional excipients may be employed for example as in thepreparation of compositions of known agents for treating the conditions.

Preferably, a pharmaceutical composition of the invention is in unitdosage form and in a form adapted for use in the medical or veterinarialfields. For example, such preparations may be in a pack form accompaniedby written or printed instructions for use as an agent in the treatmentof the conditions.

The suitable dosage range for the compounds of the invention depends onthe compound to be employed and on the condition of the patient. It willalso depend, inter alia, upon the relation of potency to absorbabilityand the frequency and route of administration.

The compound or composition of the invention may be formulated foradministration by any route, and is preferably in unit dosage form or ina form that a human patient may administer to himself in a singledosage. Advantageously, the composition is suitable for oral, rectal,topical, parenteral, intravenous or intramuscular administration.Preparations may be designed to give slow release of the activeingredient.

Compositions may, for example, be in the form of tablets, capsules,sachets, vials, powders, granules, lozenges, reconstitutable powders, orliquid preparations, for example solutions or suspensions, orsuppositories.

The compositions, for example those suitable for oral administration,may contain conventional excipients such as binding agents, for examplesyrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone;fillers, for example lactose, sugar, maize-starch, calcium phosphate,sorbitol or glycine; tabletting lubricants, for example magnesiumstearate; disintegrants, for example starch, polyvinyl-pyrrolidone,sodium starch glycollate or microcrystalline cellulose; orpharmaceutically acceptable setting agents such as sodium laurylsulphate.

Solid compositions may be obtained by conventional methods of blending,filling, tabletting or the like. Repeated blending operations may beused to distribute the active agent throughout those compositionsemploying large quantities of fillers. When the composition is in theform of a tablet, powder, or lozenge, any carrier suitable forformulating solid pharmaceutical compositions may be used, examplesbeing magnesium stearate, starch, glucose, lactose, sucrose, rice flourand chalk. Tablets may be coated according to methods well known innormal pharmaceutical practice, in particular with an enteric coating.The composition may also be in the form of an ingestible capsule, forexample of gelatin containing the compound, if desired with a carrier orother excipients.

Compositions for oral administration as liquids may be in the form of,for example, emulsions, syrups, or elixirs, or may be presented as a dryproduct for reconstitution with water or other suitable vehicle beforeuse. Such liquid compositions may contain conventional additives such assuspending agents, for example sorbitol, syrup, methyl cellulose,gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminiumstearate gel, hydrogenated edible fats; emulsifying agents, for examplelecithin, sorbitan monooleate, or acacia; aqueous or non-aqueousvehicles, which include edible oils, for example almond oil,fractionated coconut oil, oily esters, for example esters of glycerine,or propylene glycol, or ethyl alcohol, glycerine, water or normalsaline; preservatives, for example methyl or propyl p-hydroxybenzoate orsorbic acid; and if desired conventional flavouring or colouring agents.

The compounds of this invention may also be administered by a non-oralroute. In accordance with routine pharmaceutical procedure, thecompositions may be formulated, for example for rectal administration asa suppository. They may also be formulated for presentation in aninjectable form in an aqueous or non-aqueous solution, suspension oremulsion in a pharmaceutically acceptable liquid, e.g. sterilepyrogen-free water or a parenterally acceptable oil or a mixture ofliquids. The liquid may contain bacteriostatic agents, anti-oxidants orother preservatives, buffers or solutes to render the solution isotonicwith the blood, thickening agents, suspending agents or otherpharmaceutically acceptable additives. Such forms will be presented inunit dose form such as ampoules or disposable injection devices or inmulti-dose forms such as a bottle from which the appropriate dose may bewithdrawn or a solid form or concentrate which can be used to prepare aninjectable formulation.

The compounds of this invention may also be administered by inhalation,via the nasal or oral routes. Such administration can be carried outwith a spray formulation comprising a compound of the invention and asuitable carrier, optionally suspended in, for example, a hydrocarbonpropellant.

Preferred spray formulations comprise micronised compound particles incombination with a surfactant, solvent or a dispersing agent to preventthe sedimentation of suspended particles. Preferably, the compoundparticle size is from about 2 to 10 microns.

A further mode of administration of the compounds of the inventioncomprises transdermal delivery utilising a skin-patch formulation. Apreferred formulation comprises a compound of the invention dispersed ina pressure sensitive adhesive which adheres to the skin, therebypermitting the compound to diffuse from the adhesive through the skinfor delivery to the patient. For a constant rate of percutaneousabsorption, pressure sensitive adhesives known in the art such asnatural rubber or silicone can be used.

As mentioned above, the effective dose of compound depends on theparticular compound employed, the condition of the patient and on thefrequency and route of administration. A unit dose will generallycontain from 20 to 1000 mg and preferably will contain from 30 to 500mg, in particular 50, 100, 150, 200, 250, 300, 350, 400, 450, or 500 mg.The composition may be administered once or more times a day for example2, 3 or 4 times daily, and the total daily dose for a 70 kg adult willnormally be in the range 100 to 3000 mg. Alternatively the unit dosewill contain from 2 to 20 mg of active ingredient and be administered inmultiples, if desired, to give the preceding daily dose.

No unacceptable toxicological effects are expected with compounds of theinvention when administered in accordance with the invention.

The present invention also provides a method for the treatment and/orprophylaxis of the Primary and Secondary Conditions in mammals,particularly humans, which comprises administering to the mammal in needof such treatment and/or prophylaxis an effective, non-toxicpharmaceutically acceptable amount of a compound of formula (I) or apharmaceutically acceptable salt or solvate thereof.

The activity of the compounds of the present invention, as NK₃ ligands,is determined by their ability to inhibit the binding of theradiolabelled NK₃ ligands, [¹²⁵I]-[Me-Phe⁷]-NKB or [³H]-Senktide, toguinea-pig and human NK₃ receptors (Renzetti et al, 1991, Neuropeptide,18, 104-114; Buell et al, 1992, FEBS, 299(1), 90-95; Chung et al, 1994,Biochem. Biophys. Res. Commun., 198(3), 967-972).

The binding assays utilized allow the determination of the concentrationof the individual compound required to reduce by 50% the[¹²⁵I]-[Me-Phe⁷]-NKB and [³H]-Senktide specific binding to NK₃ receptorin equilibrium conditions (IC50).

Binding assays provide for each compound tested a mean IC₅₀ value of 2-5separate experiments performed in duplicate or triplicate. The mostpotent compounds of the present invention show IC₅₀ values in the range0.1-1000 nM. The NK₃-antagonist activity of the compounds of the presentinvention is determined by their ability to inhibit senktide-inducedcontraction of the guinea-pig ileum (Maggi et al, 1990, Br. J.Pharmacol., 101, 996-1000) and rabbit isolated iris sphincter muscle(Hall et al., 1991, Eur. J. Pharmacol., 199, 9-14) and human NK₃receptors-mediated Ca⁺⁺ mobilization (Mochizuki et al, 1994, .J Biol.Chem., 269, 9651-9658). Guinea-pig and rabbit in-vitro functional assaysprovide for each compound tested a mean K_(B) value of 3-8 separateexperiments, where K_(B) is the concentration of the individual compoundrequired to produce a 2-fold rightward shift in theconcentration-response curve of senktide. Human receptor functionalassay allows the determination of the concentration of the individualcompound required to reduce by 50% (IC₅₀ values) the Ca⁺⁺ mobilizationinduced by the agonist NKB. In this assay, the compounds of the presentinvention behave as antagonists.

The activity of the compounds of the present invention, as NK-2 ligands,is determined by their ability to inhibit the binding of theradiolabelled NK-2 ligands, [¹²⁵I]-NKA or [³H]-NKA, to human NK-2receptors (Aharony et al, 1992, Neuropeptide, 23, 121-130).

The binding assays utilized allow the determination of the concentrationof the individual compound required to reduce by 50% the [¹²⁵I]-NKA and[³H]-NKA specific binding to NK2 receptor in equilibrium conditions(IC₅₀).

Binding assays provide for each compound tested a mean IC₅₀ value of 2-5separate experiments performed in duplicate or triplicate. The mostpotent compounds of the present invention show IC₅₀ values in the range0.5-1000 nM, such as 1-1000 nM. The NK-2-antagonist activity of thecompounds of the present invention is determined by their ability toinhibit human NK-2 receptor-mediated Ca⁺⁺ mobilization (Mochizuki et al,1994, J. Biol. Chem., 269, 9651-9658). Human receptor functional assayallows the determination of the concentration of the individual compoundrequired to reduce by 50% (IC₅₀ values) the Ca⁺⁺ mobilization induced bythe agonist NKA. In this assay, the compounds of the present inventionbehave as antagonists.

The therapeutic potential of the compounds of the present invention intreating the conditions can be assessed using rodent disease models.

As stated above, the compounds of formula (I) are also considered to beuseful as diagnostic tool. Accordingly, the invention includes acompound of formula (I) for use as diagnostic tools for assessing thedegree to which neurokinin-3 and neurokinin-2 receptor activity (normal,overactivity or underactivity) is implicated in a patient's symptoms.Such use comprises the use of a compound of formula (I) as an antagonistof said activity, for example including but not restricted to tachykininagonist-induced inositol phosphate turnover or electrophysiologicalactivation, of a cell sample obtained from a patient. Comparison of suchactivity in the presence or absence of a compound of formula (I), willdisclose the degree of NK-3 and NK-2 receptor involvement in themediation of agonist effects in that tissue.

The following Descriptions illustrate the preparation of theintermediates, whereas the following Examples illustrate the preparationof the compounds of the invention.

DESCRIPTIONS AND EXAMPLES

DESCRIPTION A: 3-Methyl-2-phenyl-quinoline-4-carboxylic acid methylester

30 g (114 mmol) of 3-methyl-2-phenyl-quinoline-4-carboxylic acid (CAS[43071-45-0]) were suspended in 250 ml of dry CH₂Cl₂; 20 ml (230 mmol)of oxalyl chloride dissolved in 120 ml of CH₂Cl₂ were added dropwise andthe reaction mixture was stirred at room temperature for 30 min. Twodrops of N,N-dimethylformamide (DMIF) were added and the reaction wasstirred for additional 30 min. The solvent was evaporated in vacuo todryness, the residue was taken up with 100 ml of CH₂Cl₂ and 100 ml ofMeOH, dissolved in 400 ml of CH₂Cl₂, were added dropwise. After stirringfor 18 h, the solvent was evaporated in vacuo to dryness, the residuewas taken up with CH₂Cl₂ and washed with 1% NaHCO₃; the organic layerwas dried over Na₂SO₄, filtered and evaporated in vacuo to dryness toyield 31.6 g of the title compound as a solid, which was used in thefollowing reaction without further purification.

C₁₈H₁₅NO₂ MW 277.31 MP=73-75° C. IR (KBr) 3441, 3051, 2954, 1731, 1582,1556 cm⁻¹.

DESCRIPTION B: 3-Bromomethyl-2-phenyl-quinoline-4-carboxylic acid methylester

10 g (36 mmol) of 3-methyl-2-phenylquinoline-4-carboxylic acid methylester (compound of Description A) were dissolved in 500 ml of CH₃CN; 13g (72 mmol) of N-bromosuccinimide were added and the reaction mixturewas heated to reflux. After adding 1 g (4.1 mmol) of dibenzoylperoxide,the reaction was refluxed for 24 h; then additional 4 g (22.5 mmol) ofN-bromosuccinimide and 0.5 g (2.0 mmol) of dibenzoylperoxide were addedand the reaction was refluxed for 4 h. The solvent was evaporated invacuo to dryness to yield 26.1 g of crude methyl3-bromomethyl-2-phenylquinoline-4-carboxylate (theorical amount, 12.8 g)which was used in the following reaction without further purification.

C₁₈H₁₄BrNO₂ MW=356.23

DESCRIPTION 1:3-[1,4′]Bipiperidinyl-1′-ylmethyl-2-phenyl-quinoline-4-carboxylic acidmethyl ester

5 g (14 mmol) of 3-bromomethyl-2-phenyl-quinoline-4-carboxylic acidmethyl ester (compound of Description B), 2.9 g, (15.4 mmol) of 90%4-piperidinopiperidine (Aldrich), 2.7 ml (15.4 mmol) diisopropylethylamine were dissolved in 100 ml of dry THF and the mixture was stirredfor one night at 50° C. The solvent was concentrated, the residue wasdissolved in methylene chloride, washed with water, and the organicphase was dried over MgSO₄. After concentration of the solvent theresidue was purified by flash chromatography over 160 g of silicagel(eluent CH₂Cl₂/MeOH/NH₄OH: 95/5/0.5) affording 3.5 g (yield 56%) of thetitle compound as a white solid.

C₂₈H₃₃N₃O₂ MW=443.59 δ (CDCl₃): 1.29-2.02(12H); 2.25(1H); 2.47(4H);2.78(2H); 3.66(2H); 4.05(3H); 7.38-7.55(5Har); 7.58(1Har); 7.72(1Har);7.88(1Har); 8.17(1Har)ppm.

DESCRIPTION 2:3-[1,4′]Bipiperidinyl-1′-ylmethyl-2-phenyl-quinoline-4-carboxylic aciddihydrochloride

3.5 g (7.9 mmol) of3-[1,4′]bipiperidinyl-1′-ylmethyl-2-phenyl-quinoline-4-carboxylic acidmethyl ester (compound of Description 1) and 50 ml 6N HCl are refluxedfor 1.5 h. then concentrated to dryness. The residue is triturated inacetone. This process is re-applied twice to the solid thus obtainedaffording, after drying in vacuo 4.5 g of the title compound as a crudedihydrochloride used without further purification in the next step.

C₂₇H₃N₃O₂.2HCl MW=502.56 δ (DMSOd₆): 1.16-2.29(10H); 2.62-3.38(8H);4.46(2H); 5.77(1Hexch with D₂O); 7.45-8.30(9Har); 11.12 (1Hexch withD₂O)ppm.

DESCRIPTION 3:2-Phenyl-3-(4-phenyl-piperidin-1-ylmethyl)quinoline-4-carboxylic acidmethyl ester

5.4 g of crude 3-bromomethyl-2-phenyl-quinoline-4-carboxylic acid methylester (compound of Description B) were dissolved, under nitrogenatmosphere, in 30 ml of dry THF. The solution was cooled to 10° C. and4.0 g (24.8 mmol) of 4-phenylpiperidine, dissolved in 5 ml of THF, wereadded dropwise. The reaction mixture was allowed to warm to roomtemperature and stirred overnight. Salts were filtered off and thefiltrate was evaporated in vacuo to dryness, taken up with 2 N HCl andwashed with EtOAc; the aqueous layer was basified with 10% NaOH andextracted with CH₂Cl₂. The organic layer was dried over Na₂SO₄, filteredand evaporated in vacuo to dryness to obtain a crude material which waspurified by gradient flash column chromatography on 230-400 mesh silicagel, utilising a mixture of EtOAc/hexane 10:90 containing 0.5% NH₄OH(28%) as starting eluent and a mixture of EtOAc/hexane 15:85 containing0.5% NH₄OH (28%) as final eluent. 3.0 g of the title compound wererecovered as an off-white solid.

C₂₉H₂₈N₂O₂ MW=436.56 IR: (KBr) 3440, 3062, 2945, 1731, 1577, 1555 cm⁻¹.

DESCRIPTION 4:2-Phenyl-3-(4-phenyl-piperidin-1-ylmethyl)-quinoline-4-carboxylic acidhydrochloride

3.0 g (6.87 mmol) of2-phenyl-3-(4-phenyl-piperidin-1-ylmethyl)-quinoline-4-carboxylic acidmethyl ester (compound of Description 3) were dissolved in 100 ml of 6 NHCl and refluxed for 1 h. Evaporation to dryness afforded 3.5 g of crudetitle compound, which was used in the following reaction without furtherpurification.

C₂₈H₂₆N₂O₂.HCl MW=459.00 MP=175-178° C. IR: (KBr) 3385, 3062, 2495,1973, 1718, 1630 cm⁻¹.

DESCRIPTION 5:3-(4-Isopropyl-piperazin-1-ylmethyl)-2-phenylquinoline-4-carboxylic acidmethyl ester

7.8 g of crude 3-bromomethyl-2-phenyl-quinoline-4-carboxylic acid methylester (compound of Description B) were dissolved, under nitrogenatmosphere, in 130 ml of dry THF. The solution was cooled to 10° C. and2.8 g (21.6 mmol) of 1-isopropylpiperazine, dissolved in 20 ml of THF,were added dropwise. The reaction mixture was allowed to warm to roomtemperature and stirred overnight. Salts were filtered off and thefiltrate was evaporated in vacuo to dryness, taken up with 2 N HCl andwashed with EtOAc; the aqueous layer was basified with 10% NaOH andextracted with CH₂Cl₂. The organic layer was dried over Na₂SO₄, filteredand evaporated in vacuo to dryness to obtain a crude material which waspurified by flash column chromatography on 230-400 mesh silica gel,utilising a mixture of Et₂O/iPr₂O 70:30 containing 0.3% NH₄OH (28%). 3.8g of the title compound were recovered as a yellow solid.

C₂₅H₂₉N₃O₂ MW=403.54 IR: (KBr) 3441, 3065, 2946, 1731, 1580, 1555 cm⁻¹.

DESCRIPTION 6:3-(4-Isopropyl-piperazin-1-ylmethyl)-2-phenyl-quinoline-4-carboxylicacid dihydrochloride

3.8 g (9.42 mmol) of3-(4-isopropyl-piperazin-1-ylmethyl)-2-phenyl-quinoline-4-carboxylicacid methyl ester (compound of Description 5) were dissolved in 100 mlof 6 N HCl and refluxed for 4 h. Evaporation to dryness afforded 4.0 gof crude title compound, which was used in the following reactionwithout further purification.

C₂₄H₂₇N₃O₂.2HCl MW=389.50 MP=177-180° C. IR: (KBr) 3408, 2928, 2666,1716, 1632 cm⁻¹.

DESCRIPTION 7: (S)-1-Cyclohexyl-propylamine hydrochloride

2.0 g (14.8 mmol) of (S)-1-phenyl-propylamine were dissolved in 250 mlof a 4% solution of citric acid in H₂O. 0.6 g of 20% Pd(OH)₂/C wereadded and the reaction mixture was hydrogenated in a steel autoclave at50 bar and 60° C. for 24 h. The catalyst was filtered off, the filtratewas evaporated and the residue was taken up with 40% NaOH and extractedseveral times with H₂O. The combined organic layers were dried overNa₂SO₄ and acidified with HCl/Et₂O. Evaporation to dryness afforded 0.3g of the title compound as a solid.

C₉H₁₉N.HCl MW=389.50

DESCRIPTION 8:3-(4-Fmoc-piperazin-1-ylmethyl)-2-phenyl-quinoline-4-carboxylic acidmethyl ester

6.6 g (18.5 mmol) of 3-bromomethyl-2-phenyl-quinoline-4-carboxylic acidmethyl ester (compound of Description B) were reacted with 6.8 g (20mmol) of Fmoc piperazine in 150 ml of THF following the procedure usedin Description 3 and afforded 7.5 g (yield: 69%) of the title compound.

C₃₇H₃₃N₃O₄ MW=583.68 ¹H NMR δ (DMSOd₆): 1.99(4H); 3.10(4H); 3.62(2H);3.97(3H); 4.20(1H); 4.42(2H); 7.18-7.40(4Har); 7.45-7.92(12Har);8.09(1Har)ppm.

DESCRIPTION 9:3-(4-Fmoc-piperazin-1-ylmethyl)-2-phenyl-quinoline-4-carboxylic acidhydrochloride

7.5 g (13 mmol) of the ester of Description 8 are hydrolysed with 6 Naqueous hydrochloric acid following the procedure used in Description 4affording 9.5 g of crude title compound which was used withoutpurification in the next step.

C₃₆H₃₁N₃O₄.HCl MW=606.12 ¹H NMR δ (DMSOd₆): 2.50(4H); 3.32(4H);4.22(2H); 4.23(1H); 4.35(2H); 6.50(1Hexch with D₂O); 7.22-7.88(14Har);7.98(1Har); 8.17(2Har)ppm.

DESCRIPTION 10:3-(4-Fmoc-piperazin-1-ylmethyl)2-phenyl-quinoline-4-carboxylic acid((S)-1-phenyl-propyl)-amide

5.35 g (8.3 mmol) of crude acid of Description 9 were condensed on 1.7ml (12.5 mmol) of (S)-1-phenyl-propylamine following the procedure ofExample 2 affording, after flash chromatography on silica gel, 3.2 g(56%) of the title compound.

C₄₅H₄₂N₄O₃ MW=686.86 ¹H NMR δ(DMSOd₆): 0.94(3H); 1.40-2.18(6H);2.57-3.13(4H); 3.50(2H); 4.21(1H); 4.34(2H); 5.08(1H); 7.09-7.98(21Har);8.03(1Har): 9.12(1Hexch with D₂O)ppm.

DESCRIPTION 11:3-(4-Fmoc-piperazin-1-ylmethyl)-2-phenyl-quinoline-4-carboxylic acid((S)-1-cyclohexyl-ethyl)-amide

4.75 g (8.3 mmol) of crude acid of Description 9 were condensed on 1.65ml (11 mmol) of (S)-1-cyclohexyl-ethylamine following the procedure ofExample 2 affording, after flash chromatography on silica gel, 2.2 g(yield 43.9%) of the title compound.

C₄₄H₄₆N₄O₃ MW=678.87 ¹H NMR δ(DMSOd₆): 0.95(3H); 1.68-4.00(21H);2.60(3H); 5.08(1H); 7.22-8.24(13Har); 8.11(1Har); 9.32(1Hexch with D2O);10.82(2Hexch with D₂O)ppm.

DESCRIPTION 12:3-(4-Fmoc-piperazin-1-ylmethyl)-2-phenyl-quinoline-4-carboxylic acid((S)-2-methyl-1-phenyl-propyl)-amide

6.95 g (10.8 mmol) of crude acid of Description 9 were condensed on 2 g(13.5 mmol) of (S)-2-methyl-1-phenyl propylamine following the procedureof Example 2 affording, after flash chromatography on silica gel, 5.4 g(yield 71%) of the title compound.

C₄₆H₄₄N₄O₃ MW=700.86 ¹H NMR δ(CDCl₃): 0.96(3H); 1.18(3H); 1.56-2.98(4H);2.28(1H); 3.04(4H); 3.53(2H); 4.20(1H); 4.35(2H); 5.17(1H);7.18-7.63(18Har); 7.74(3Har); 7.97(1Hexch with D₂O); 8.14(1Har)ppm.

DESCRIPTION 13: 2-Phenyl-3-piperazin-1-ylmethyl-quinoline-4-carboxylicacid ((S)-2-methyl-1-phenyl-propyl)-amide

5.4 g (7.7 mmol) of the Fmoc derivative of Description 12 was reactedwith 1.25 ml of piperidine in 200 ml acetonitrile, at room temperaturefor one night. The reaction mixture is concentrated to dryness and theresidue was purified by flash chromatography on silicagel (eluant:CH₂Cl₂/CH₃OH/NH₄OH; 90/10/2), affording 2.55 g (yield 69.3%) of thetitle compound.

C₃₁H₃₄N₄O MW=478.64 ¹H NMR δ(DMSOd₆): 0.79(3H); 1.06(3H); 1.49-2.55(9H);3.45(2H and 1Hexch with D2O); 4.88(1H); 7.12-8.10(14Har); 9.16(1Hexchwith D₂O)ppm.

DESCRIPTION 14: 2-Phenyl-3-piperazin-1-ylmethyl-quinoline-4-carboxylicacid ((S)-1-phenyl-propyl)-amide

2.75 g (41 mmol) of the Fmoc protected derivative of Description 12afforded by applying the procedure of Description 13, 1.14 g (yield 60%)of the title compound.

C₃₀H₃₂N₄O MW=464.61 ¹H NMR δ (DMSOd₆): 0.94(3H); 1.57-2.08(6H);2.31(4H); 3.36(2H and 1Hexch with D₂O); 5.07(1H); 7.13-7.94(13Har);8.01(1Har); 9.17(1Hexch with D₂O)ppm.

DESCRIPTION 15:3-[4-(1-Cyanoimino-1-methylsulfanyl-methyl)-piperazin-1-ylmethyl]-2-phenyl-quinoline-4carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide

0.5 g (1.1 mmol) of2-phenyl-3-piperazin-1-ylmethyl-quinoline-4-carboxylic acid((S)-1-cyclohexyl-ethyl)-amide (compound of Example 34) and 0.16 g (1.1mmol) of dimethyl N-cyanodithioiminocarbonate (Aldrich) were heated atreflux for 6 h in a mixture of 2.2 ml of DMF and 8.8 ml of EtOH. Thesolvent was concentrated and the residue purified by flashchromatography on silicagel (CH₂Cl₂/MeOH: 98/2) affording 0.56g (yield91.8%) of the title compound which was used without purification in thefollowing step.

C₃₃H₃₄N₆OS MW=562.74 ¹HNMR δ(CDCl₃): 1.00-1.39(5H); 1.24(3H); 1.48(1H);1.63-1.96(5H); 2.25(4H); 2.69(3H); 3.57(4H); 3.72(2H); 4.25(1H);6.42(1Hexch with D₂O; 7.38-7.55(5Har); 7.60(1Har); 7.75(1Har);7.95(1Har); 8.14(1Har)ppm.

DESCRIPTION 16:3-[4-(1-Methanesulfonylimino-1-methylsulfanyl-methyl)-piperazin-1-ylmethyl]-2-phenyl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide

0.48 g (1.05 mmol) of2-phenyl-3-piperazin-1-ylmethyl-quinoline-4-carboxylic acid((S)-1-cyclohexyl-ethyl)-amide (compound of Example 34) and 0.21 g (1.05mmol) of carbonimidodithioic acid, (methylsulfonyl)-dimethyl ester (RN13068-10-5) were heated at reflux for 5 h in a mixture of 2 ml of DMFand 8 ml of EtOH. The solvent was concentrated and the residue purifiedby flash chromatography on silicagel (CH₂Cl₂/MeOH: 97/3) affording 0.52g of crude title compound which was used without purification in thefollowing step.

C₃₃H₃₇N₄O₃S₂ MW=615.82 ¹H NMR δ(CDC₃): 0.95-1.38(5H); 1.28(3H);1.48(1H); 1.62-1.94(5H); 2.28(4H); 2.47(3H); 3.01(3H); 3.54(4H);3.59(2H); 4.25(1H); 6.52(1Hexch with D₂O); 7.36-7.53(5Har); 7.59(1Har);7.75(1Har); 7.95(1Har); 8.14(1Har)ppm.

DESCRIPTION 17:4-[4((S)-1-Cyclohexyl-ethylcarbamoyl)-2-phenyl-quinolin-3-ylmethyl]-N-methyl-piperazine-1-carboximidothioicacid methyl ester

0.05 g (0.95 mmol) of3-(4-methylthiocarbamoyl-piperazin-1-ylmethyl)-2-phenyl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide (compound of Example 75) wassuspended in 5 ml acetone and 0.41 g (2.85 mmol) methyl iodide wasadded. After 4 h stirring at room temperature the mixture became clear.The solvent was concentrated and the residue triturated with di-ethylether affording, after filtration and drying, 0.63 g of the hydroiodidesalt of the title compound. This compound was used without furtherpurification in the next step.

C₃₃H₃₇N₅OS MW=551.76 ¹H NMR δ(DMSOd₆): 0.92-1.36(5H); 1.75(3H);1.47(1H); 1.58-1.92(5H); 2.24(4H); 2.46(3H); 3.05(3H); 3.36(4H);3.63(2H); 4.02(1H); 7.36-7.91(8Har); 8.04(1Har); 8.55(1Hexch withD₂O)ppm.

DESCRIPTION 18:3-(4-Oxo-piperidin-1-ylmethyl)-2-phenyl-quinoline-4-carboxylic acid((S)-1-phenyl-propyl)-amide

Starting from 3-bromomethyl-2-phenylquinoline-4-carboxylic acid methylester (compound of Description B) and 4-oxopiperidine, following theprocedure of description 1, then applying procedures analogous to thosedescribed in description 2 and example 2 afforded the title compoundafter purification on silicagel (EtOAc/Heptane: 1/1).

C₃₁H₃₁N₃O₂ MW=477.60 ¹H NMR δ(DMSOd₆): 0.83(3H); 1.57-2.30(8H);2.45(2H); 3.34-3.98(2H); 5.08(1H); 7.12-8.18(14Har); 9.21(1Hexch withD₂O)ppm.

DESCRIPTION 19: 4-tert-Butylsulfamoyl-piperazine-1-carboxylic acidtert-butyl ester

6.1 g (32.62 mmol) of piperazine-1-carboxylic acid tert-butyl ester (RN76535-74-5) were dissolved in 150 ml of CH₂Cl₂ and 4.5 g (32.6 mmol) ofK₂CO₃ were added. The mixture was cooled to 0° C. and 5.6 g (32.62 mmol)of tert-butyl-sulfamoylchloride (prepared according to Catt, J. D. JOC,1974, 39, 566-8) dissolved in 50 ml of CH₂Cl₂ were added dropwise andthe reaction mixture was stirred at room temperature for 2 h. 50 ml ofwater were added, the two phase separated in a separatory funnel and theaqueous phase extracted with CH₂Cl₂. The organic phases were collected,dried over Na₂SO₄ and evaporated in vacuo to dryness to yield 4.6 g ofthe title compound as a yellow solid

C₁₃H₂₇N₃O₄S MW=321.43 IR: (KBr) 3273, 2971, 1701, 1364, 1137, 1023, 934,768 cm⁻¹.

DESCRIPTION 20: 4-Dimethylsulfamoyl-piperazine-1-carboxylic acidtert-butyl ester

Prepared as described in Description 19 from 10.38 g (55.7 mmol) ofpiperazine-1-carboxylic acid tert-butyl ester (RN 76535-74-5), 7.7 g(55.7 mmol) of K₂CO₃ and 8 g (55.7 mmol) of dimethyl-sulfamoylchloride15.2 g of the title compound were obtained as a yellow solid

C₁₁H₂₃N₃O₄S MW=293.39 IR: (KBr) 2979, 2866, 1687, 1142, 952, 752 cm⁻¹.

DESCRIPTION 21: Piperazine-1-sulfonic acid tert-butylamide

4.6 g (14.3 mmol) of 4-tert-butylsulfamoyl-piperazine-1-carboxylic acidtert-butyl ester (compound of Description 19) were dissolved in 10 ml ofCH₂Cl₂ and 50 ml of 30% ethereal HCl were added. The solution wasstirred at room temperature for 2 h. The solvent was evaporated in vacuoto dryness yielding 1.5 g of the title compound as a white solid

C₈H₁₉N₃O₂S MW=221.32 IR: (KBr) 3207, 2730, 1591, 1326, 1143, 1001, 917,720, 631 cm⁻¹.

DESCRIPTION 22: Piperazine-1-sulfonic acid dimethylamide

13 g (44.31 mmol) of 4-dimethylsulfamoyl-piperazine-1-carboxylic acidtert-butyl ester (compound of Description 20) were dissolved in 100 mlof CH₂Cl₂ and 20 ml of 30% ethereal HCl were added. The solution wasstirred at room temperature for 2 h. The solvent was evaporated in vacuoto dryness yielding 9.2 g of the title compound as a white solid

C₆H₁₅N₃O₂S MW=193.27 IR: (KBr) 2786, 1688, 1356, 1152, 1037, 942, 867,737,677 cm⁻¹.

DESCRIPTION 23:3-(4-tert-Butylsulfamoyl-piperazin-1-ylmethyl)-2-phenyl-quinoline-4-carboxylicacid methyl ester

1.5 g (6.78 mmol) of piperazine-1-sulfonic acid tert-butylamide(compound of Description 21) and 0.94 g (6.78 mmol) of K₂CO₃ weresuspended in 70 ml of CH₃CN. 2.42 g (6.78 mmol) of3-bromomethyl-2-phenylquinoline-4-carboxylic acid methyl ester (compoundof Description B) were dissolved in 30 ml of CH₃CN and the solution wasadded to the previous suspension. The resulting mixture was stirred atroom temperature for 4 h. The solvent was evaporated in vacuo todryness, the residue was taken up with 6N HCl and washed with EtOAc. Theaqueous phase was basified with 1 N NaOH and extracted with EtOAc. Theorganic phase was dried over Na₂SO₄ and evaporated to dryness to yield a3.0 of crude title compound used without further purification

C₂₆H₃₂N₄O₄S MW=496.63 IR: (KBr) 3280, 2974, 1734, 1575, 1555, 1444,1220, 1146, 940 764 cm⁻¹.

DESCRIPTION 24:3-(4-Dimethylsulfamoyl-piperazin-1-ylmethyl)-2-phenyl-quinoline-4-carboxylicacid methyl ester

1.6 g (8.24 mmol) of piperazine-1-sulfonic acid dimethylamide (compoundof Description 22) and 1.16 g (8.42 mmol) of K₂CO₃ were suspended in 70ml of CH₃CN. 3.0 g (8.42 mmol) of3-bromomethyl-2-phenylquinoline-4-carboxylic acid methyl ester (compoundof Description B) were dissolved in 30 ml of CH₃CN and the solution wasadded to the previous suspension. The resulting mixture was stirred atroom temperature for 4 h. The solvent was evaporated in vacuo todryness, the residue was taken up with 6N HCl and washed with EtOAc. Theaqueous phase was basified with 1 N NaOH and extracted with EtOAc. Theorganic phase was dried over Na₂SO₄ and evaporated to dryness to yield acrude material which was purified by flash column chromatography on230-400 mesh silica gel, utilising a mixture of EtOAc/hexane 3:7 aseluent. After evaporation of the solvent, 3.0 g of the title compound asa yellow solid were obtained.

C₂₄H₂₈N₄O₄S MW=468.58 IR: (KBr) 2938, 1736, 1574, 1552, 1452, 1244,1156, 942 748 cm⁻¹.

DESCRIPTION 25:2-Phenyl-3-(4-sulfamoyl-piperazin-1-ylmethyl)-quinoline-4-carboxylicacid

3.0 g (6.04 mmol) of3-(4-tert-butylsulfamoyl-piperazin-1-ylmethyl)-2-phenyl-quinoline-4-carboxylicacid methyl ester (compound of Description 23) were suspended in 50 mlof 6N HCl and the mixture was refluxed for 4 h. The solvent wasevaporated in vacuo to dryness. For three times the residue was treatedwith Et₂O and the solvent was evaporated to dryness to yield 3.0 ofcrude title compound used without further purification

C₂₁H₂₂N₄O₄S MW=426.44 IR: (KBr) 3281,2974, 1734,1556, 1221, 1146,1056,941, 765 cm⁻¹.

DESCRIPTION 26:3-(4-Dimethylsulfamoyl-piperazin-1-ylmethyl)-2-phenyl-quinoline-4-carboxylicacid

3.0 g (6.40 mmol) of3-(4dimethylsulfamoyl-piperazin-1-ylmethyl)-2-phenyl-quinoline-4-carboxylicacid methyl ester (compound of Description 24) were suspended in 50 mlof 6N HCl and the mixture was refluxed for 4 h. The solvent wasevaporated in vacuo to dryness. After trituration of the residue withMe₂CO, 1.4 g of the title compound were recovered as a pale yellow solidused without further purification.

C₂₃H₂₆N₄O₄S MW=454.55 R: (KBr) 3427, 2658, 1726, 1632, 1581, 1452, 1344,1151, 932 745 cm⁻¹.

DESCRIPTION 27: 7-Methoxy-3-methyl-2-phenyl-quinoline-4-carboxylic acidmethyl ester

16 g (54.5 mmol) of 7-methoxy-3-methyl-2-phenyl-quinoline-4-carboxylicacid (prepared analogously to starting material of Description A) weresuspended in 400 ml of dry CH₂Cl₂ and 9.52 ml (126.93 mmol) of oxalylchloride were added dropwise. Two drops of N,N-dimethylformamide (DMF)were added and the reaction mixture was stirred for 3 h at roomtemperature. The solvent was evaporated in vacuo to dryness, the residuewas taken up with 150 ml of CH₂Cl₂ and quickly dropped in a solution of200 ml of MeOH and 200 ml of CH₂Cl₂. After stirring for 1 h, the solventwas evaporated in vacuo to dryness, the residue was taken up with EtOAcand washed with 1% NaHCO₃; the organic layer was dried over Na₂SO₄,filtered and evaporated in vacuo to dryness. After trituration of theresidue with Et₂O, 19 g of the title compound were recovered as a darkpowder used without further purification.

C₁₉H₁₇NO₃ MW=307.35 IR (KBr) 3067,2947, 1918, 1729,1634, 1581, 1246, 846cm⁻¹.

DESCRIPTION 28:3-[1,4′]Bipiperidinyl-1′-ylmethyl-8-bromo-7-methoxy-2-phenyl-quinoline-4-carboxylicacid methyl ester

Prepared as described in Description B and Description 1 from 4.7 g(15.3 mmol) of 7-methoxy-3-methyl-2-phenyl-quinoline-4-carboxylic acidmethyl ester (compound of Description 27), 5.5 g (30.6 mmol) ofN-bromosuccinimide, 0.5 g (2.05 mmol) of dibenzoylperoxide, 3.85 g (23mmol) of 4-piperidinopiperidine and 3.18 g ( 23.0 mmol) of K₂CO₃, bystirring in CH₃CN at room temperature for 4 h. 6.2 g of the titlecompound were obtained.

C₂₉H₃₄BrN₃O₃ MW=552.51 IR (KBr) 3370,2938, 1712, 1612, 1352, 1268,1174,704cm⁻¹.

DESCRIPTION 29:3-[1,4′]Bipiperidinyl-1′-ylmethyl-8-bromo-7-methoxy-2-phenyl-quinoline-4-carboxylicacid hydrochloride

Prepared as described in Description 4 from 6.0 g (10.9 mmol) of3-[1,4′]bipiperidinyl-1′-ylmethyl-8-bromo-7-methoxy-2-phenylquinoline-4-carboxylicacid methyl ester (compound of Description 28) and 50 ml of 6 N HClyielding 4.7 g of a slightly brown powder.

C₂₈H₃₂BrN₃O₃.HCl MW=574.94 IR: (KBr) 3453,2939, 2532, 1714, 1607, 1598,1271, 1072,960, 779, 705, cm⁻¹.

DESCRIPTION 30:3-[1,4′]Bipiperidinyl-1′-ylmethyl-8-chloro-7-methoxy-2-phenyl-quinoline-4-carboxylicacid methyl ester

Prepared as described in Description B and Description 1 from 9.0 g(29.3 mmol) of 7-methoxy-3-methyl-2-phenyl-quinoline-4-carboxylic acidmethyl ester hydrochloride (compound of Description 27 HCl), 10.4 g(58.6 mmol) of N-bromosuccinimide, 1.0 g (4.10 mmol) ofdibenzoylperoxide 9.9 g (58.6 mmol) of 4-piperidinopiperidine and 3.18 g( 23.0 mmol) of K₂CO₃. Purified by flash column chromatography on230-400 mesh silica gel, utilising a mixture of EtOAc/MeOH 9:1containing 0.1% NH₄OH (28%) affording 1.7 g of the title compound.

C₂₉H₃₄ClN₃O₃ MW=508.06 IR (KBr) 2934, 1730, 1610, 1501, 1238, 1079, 774,706 cm⁻¹.

DESCRIPTION 31:3-[1,4′]Bipiperidinyl-1′-ylmethyl-8-chloro-7-hydroxy-2-phenyl-quinoline-4-carboxylicacid dihydrobromide

1.5 g (3.0 mmol) of3-[1,4′]bipiperidinyl-1′-ylmethyl-8-chloro-7-methoxy-2-phenyl-quinoline-4-carboxylicacid methyl ester (compound of Description 30) were dissolved in 50 mlof 48% HBr and the solution was refluxed for 8 h. The solvent wasevaporated in vacuo to dryness yielding 2.2 g of the crude titlecompound as a dark powder used without further purification.

C₂₇H₃₁ClN₃O₃.2HBr MW=736.76 IR: (KBr) 2948, 1725, 1624, 1226, 959, 705cm⁻¹.

The following Examples illustrate the invention; Table 1 summarizes allthe compounds of the Examples 1-95 and their analytical data; Table 2describes NMR spectroscopic data of Examples 1-95 and Table 3illustrates chemical names of compounds of Examples 1-95.

EXAMPLE 22-Phenyl-3-(4-phenyl-piperidin-1-ylmethyl)-quinoline-4-carboxylic acid((S)-1-phenyl-propyl)-amide

2.5 g (5.0 mmol) of crude2-phenyl-3-(4-phenyl-piperidin-1-ylmethyl)-quinoline-4-carboxylic acidhydrochloride (compound of Description 4) were dissolved in 50 ml of dryTHF; 1.1 ml (7.8 mmol) of triethylamine (TEA) and 2.4 g (6.5 mmol) ofO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluroniumhexafluoro-phosphate(HBTU) were added and the reaction mixture was cooled at 0° C. 0.72 ml(5 mmol) of (S)-1-phenyl-propylamine, dissolved in 20 ml of dry CH₂Cl₂,were added dropwise and the reaction mixture was stirred at roomtemperature for 24 h and at 50° C. for 2 h. The solvent was evaporatedin vacuo to dryness and the residue was taken up with EtOAc and washedwith H₂O, 1 N NaOH and brine, dried over Na₂SO₄ and evaporated todryness to yield a crude material which was purified by gradient flashcolumn chromatography on 230-400 mesh silica gel, utilising a mixture ofEtOAc/hexane 3:7 as starting eluent, and a mixture of EtOAc/hexane 4:6as final eluent. After trituration with iPr₂O, 1.0 g of the titlecompound were recovered as a pale yellow solid used without furtherpurification.

C₃₇H₃₇N₃O MW=539.72 IR: (KBr) 3279, 3060, 3028, 2931, 1633, 1536, 1494,757, 699 cm⁻¹.

EXAMPLE 43-(4-Isopropyl-piperazin-1-ylmethyl)-2-phenyl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide dihydrochloride

2.3 g (5.0 mmol) of crude3-(4-isopropyl-piperazin-1-ylmethyl)-2-phenyl-quinoline-4-carboxylicacid dihydrochloride (compound of Description 6) were dissolved in 200ml of a 1:1 mixture of CH₂Cl₂/CH₃CN; 2.0 ml (15 mmol) of triethylamine(TEA) and 2.5 g (6.5 mmol) ofO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluroniumhexafluorophosphate(HBTU) were added and the reaction mixture was cooled at 0° C. 0.74 ml(5 mmol) of (S)-1-cyclohexyl-ethylamine, dissolved in 10 ml of dryCH₂Cl₂, were added dropwise and the reaction mixture was stirred at roomtemperature for 24 h. The solvent was evaporated in vacuo to dryness andthe residue was taken up with EtOAc and washed with H₂O, 1 N NaOH andbrine, dried over Na₂SO₄ and evaporated to dryness to yield a crudematerial which was purified by flash column chromatography on 230-400mesh silica gel, utilising a mixture of CH₂Cl₂/MeOH 95:5 containing 0.5%NH₄OH (28%). The residue was dissolved in acetone and acidified withHCl/Et₂O; the precipitate so formed was recovered by suction filtrationto yield 0.9 g of the title compound as a yellow solid.

C₃₂H₄₂N₄O.2HCl MW=571.64 IR: (KBr) 341 1; 2927; 2851; 2667; 1650; 1546cm⁻¹.

EXAMPLE 133-[1,4′]Bipiperidinyl-1′-ylmethyl-2-phenyl-quinoline-4-carboxylic acid((S)-1-cyclohexyl-ethyl)-amide dihydrochloride

4.0 g (8.0 mmol) of crude3-[1,4′]bipiperidinyl-1′-ylmethyl-2-phenyl-quinoline-4-carboxylic aciddihydrochloride (compound of Description 2) were dissolved in 300 ml ofa 1:1 mixture of CH₂Cl₂/CH₃CN; 3.4 ml (24.6 mmol) of triethylamine (TEA)and 4.0 g (10.7 mmol) ofO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluroniumhexafluorophosphate(HBTU) were added and the reaction mixture was cooled at 0° C. 1.22 ml(8.2 mmol) of (S) 1-cyclohexylethylamine, dissolved in 10 ml of dryCH₂Cl₂, were added dropwise and the reaction mixture was stirred at roomtemperature for 24 h. Additional 2.0 g (5.3 mmol) of HBTU and 2.0 ml(13.4 mmol) of (S)-1-cyclohexyl-ethylamine were added and the reactionmixture was heated to 40° C. for 8 h. The solvent was evaporated invacuo to dryness and the residue was taken up with EtOAc and washed withH₂O, 1 N NaOH and brine, dried over Na₂SO₄ and evaporated to dryness toyield a crude material which was purified by flash column cromatographyon 230-400 mesh silica gel, utilising a mixture of EtOAc/MeOH 95:5containing 0.5% NH₄OH (28%). The residue was dissolved in acetone andacidified with HCl/Et₂O; the precipitate so formed was recovered bysuction filtration to yield 3.2 g of title compound as a pale yellowsolid.

C₃₅H₄₆N₄O.2HCl MW=611.70 IR: (KBr) 3422, 2928, 2852, 2659, 1647, 1546cm⁻¹.

EXAMPLE 34 2-Phenyl-3-piperazin-1-ylmethyl-quinoline-4carboxylic acid((S)-1-cyclohexyl-ethyl)-amide

Synthesised starting from the compound of Description 11 and followingthe procedure of Description 13.

C₂₉H₃₆N₄O MW=456.63

EXAMPLE 473-[4-3-Diethylamino-propanoyl)-piperazin-1-ylmethyl]-2-phenyl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide

0.4 g (0.88 mmol) of2-phenyl-3-piperazin-1-ylmethyl-quinoline-4-carboxylic acid((S)-1-cyclohexyl-ethyl)-amide (compound of Example 34), 0.5 g (1.3mmol) of HBTU, 360 microliters (2.5 mmol) of triethyl amine and 240 mgof 3-diethylaminopropionic acid were dissolved in 10 ml of anhydrous THFand were stirred 16 hours at room temperature. The solvent wasconcentrated to dryness and the residue was dissolved in 20 ml of EtOAcand washed with water then with 0.5 N aqueous NaOH and again with water.The organic phase was dried over MgSO₄, concentrated to dryness. Theresidue was purified by flash chromatography on silicagel (CH₂Cl₂/MeOH:90/10). The fractions containing the desired compound were concentratedand the residue was crystallised from di-isopropyl ether affording 250mg (yield 48.7%) of the title compound as white crystals.

C₃₆H₄₉N₅O₂ MW=583.82

EXAMPLE 53({4-[4-((S)-1-Cyclohexyl-ethylcarbamoyl)-2-phenyl-quinolin-3-ylmethyl]-piperazin-1-yl}-dimethylamino-methylene)-dimethyl-ammoniumhexafluorophosphate

50 mg (0.11 mmol) of the piperazine of Example 34 were reacted with 62mg (0.16 mmol) of HBTU and 18 mg (0.17 mmol) of triethylamine in amixture of 1.2 ml of anhydrous THF and 1 ml of CH₂Cl₂. This mixture wasstirred 48 h at room temperature, then concentrated to dryness. Theresidue was dissolved in 1 ml of water and 1 ml of ethyl acetate. Theaqueous phase was extracted twice with EtOAc, washed twice with water,dried over MgSO₄, concentrated to dryness. The residue was purified byflash chromatography on silicagel (CH₂Cl₂/MeOH: 95/5) to afford 43 mg ofthe title compound as a white solid (yield 55.8%).

C₃₄H₄₇N₆O.PF₆ MW=700.75

EXAMPLE 553-(4-Amino-piperidin-1-ylmethyl)-2-phenyl-quinoline-4-carboxylic acid((S)-1-phenyl-propyl)-amide

0.477 g (1 mmol) of3-(4-oxo-piperidin-1-ylmethyl)-2-phenyl-quinoline-4-carboxylic acid((S)-1-phenyl-propyl)-amide (compound of Description 18), 0.462 g (6mmol) of ammonium acetate were dissolved in 10 ml of methanol andstirred at room temperature for 1 h. Then 0.08 g of sodiumcyanoborohydride were added and the mixture was stirred one night atroom temperature. The reaction mixture was poured in 50 ml of water andthe formed precipitate was filtered off. The aqueous phase was extractedwith methylene chloride. The collected solid was dissolved in methylenechloride, both organic phases merged, washed with water, dried overMgSO₄, concentrated to dryness. The residue was purified by micro flashchromatography on silicagel (CH₂Cl₂/MeOH/NH₄OH: 90/10/1) to afford 47 mgof the title compound as a white solid (yield ca 10%).

C₃₁H₃₄N₄O MW=478.64

EXAMPLE 663-[1,4′]Bipiperidinyl-1′-ylmethyl-8-bromo-7-methoxy-2-phenyl-quinoline-4-carboxylicacid ((S)-1-phenyl-propyl)-amide

Prepared as described in Example 2 from 2 g (3.7 mmol) of3-[1,4′]bipiperidinyl-1′-ylmethyl-8-bromo-7-methoxy-2-phenyl-quinoline-4-carboxylicacid (compound of Description 29), 1.55 ml (11.1 mmol) of triethylamine(TEA) 1.82 g (4.8 mmol) ofO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluroniumhexa-fluorophosphate(HBTU) and 0.75 g (5.5 mmol) of (S)-1-phenyl-propylamine The crudematerial was purified by flash column chromatography on 230-400 meshsilica gel, utilising a mixture of EtOAc/MeOH 95:5 containing 0.05%NH₄OH (28%) affording 0.4 g of title compound. After trituration withiPr₂O, 0.3 g of the title compound were recovered as a pale yellowsolid.

C₃₇H₄₃BrN₄O₂ MW=655,68 IR: (KBr) 3278, 2936, 1641, 1276, 1073, 845,702cm⁻¹.

EXAMPLE 673-[1,4′]Bipiperidinyl-1′-ylmethyl-7-methoxy-2-phenyl-quinoline-4-carboxylicacid ((S)-1-phenyl-propyl)-amide hydrochloride

0.2 g (0.31 mmol) of3-[1,4′]Bipiperidinyl-1′-ylmethyl-8-bromo-7-methoxy-2-phenyl-quinoline-4-carboxylicacid ((S)-1-phenyl-propyl)-amide (compound of Example 66) and 0.43 ml(0.31 mmol) of TEA were dissolved in 100 ml of EtOH. 20 mg of 10%Palladium on charcoal were added under nitrogen atmosphere and themixture was hydrogenated at 1 psi for 3 h. The catalyst was filteredoff, the solvent was evaporated in vacuo to dryness and the residue waspurified by gradient flash column chromatography on 230-400 mesh silicagel, utilising EtOAc containing 0.05% NH₄OH (28%) as starting eluent,and a mixture of EtOAc/MeOH 95:5 containing 0.05% NH₄OH (28%) as finaleluent. The residue was dissolved in acetone and acidified withHCl/Et₂O; the precipitate so formed was recovered by suction filtrationto yield 0.1 g of the title compound as a pale yellow solid.

C₃₇H₄₄N₄O₂ MW=576.78 IR: (KBr) 3239, 2943, 2530, 1619, 1534, 1222, 1027,844, 703 cm⁻¹.

EXAMPLE 723-[4-(3,4-Dioxo-2-pyrrolidin-1-yl-cyclobut-1-enyl)-piperazin-1-ylmethyl]-2-phenyl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide

0.25 g (0.55 mmol) of2-phenyl-3-piperazin-1-ylmethyl-quinoline-4-carboxylic acid((S)-1-cyclohexyl-ethyl)-amide (compound of Example 34) and 0.124 g(0.55 mmol) of 3,4-di-N-butoxy-3-cyclobuten-1,2-dione (Aldrich) werestirred in 3 ml of ethanol at room temperature for 7 h. Then, 0.15 g(2.2 mmol) of pyrrolidine was added and stirring was continued for onenight. The mixture was concentrated in vacuo and the residue waspurified by flash chromatography on silicagel (CH₂Cl₂/MeOH: 98/2). Afterconcentration of the desired fractions, the residue was crystallisedfrom di-isopropyl ether. The solid obtained was purified again bychromatography on silicagel (EtOAc as eluent). After concentration ofthe desired fractions the residue was re-crystallised from di-isopropylether to afford 0.180 g (yield 54%) of the title compound as whitecrystals. C₃₇H₄₃N₅O₃ MW=605.78

EXAMPLE 753-(4-Methylthiocarbamoyl-piperazin-1-ylmethyl)-2-phenyl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide

0.4 g (0.87 mmol) of2-phenyl-3-piperazin-1-ylmethyl-quinoline-4carboxylic acid((S)-1-cyclohexyl-ethyl)-amide (compound of Example 34) were dissolvedin 10 ml of methylene chloride and 0.09 g methylisothiocyanate wereadded. The mixture was stirred for 5 h at room temperature and thesolvent was concentrated in vacuo and the residue was purified by flashchromatography on silicagel (EtOAc/heptane: 95/5) to afford 0.43 g(yield 92%) of the title compound as white crystals.

C₃₁H₃₉N₅OS MW=529.75

EXAMPLE 763-[4-(1-Cyanoimino-1-pyrrolidin-1-yl-methyl)-piperazin-1-ylmethyl]-2-phenyl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide

0.25 g (0.45 mmol) of3-[4-1-cyanoimino-1-methylsulfanyl-methyl)-piperazin-1-ylmethyl]-2-phenyl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide (compound of Description 15) and 1.5ml of pyrrolidine were heated to reflux for 2 h. The excess ofpyrrolidine was removed in vacuo and the residue was purified by flashchromatography on silicagel (EtOAc/CH₂Cl₂: 80/20). After concentrationof the desired fractions the residue was crystallised from di-isopropylether to afford 0.195 g (yield 75%) of the title compound as whitecrystals.

C₃₅H₄₃N₇O MW=577.77

EXAMPLE 783-[4-(1-Methylimino-1-pyrrolidin-1-yl-methyl)-piperazin-1-ylmethyl]-2-phenyl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide

0.2 g (ca 0.3 mmol) of the crude salt of Description 17 was dissolved in10 ml of acetonitrile and 1 g of pyrrolidine and 1.5 g of KF were added.The mixture was refluxed for one night. After prolonged concentrationunder vacuum, the residue was dissolved in methylene chloride and thesolid filtered off and discarded. The solution was concentrated and theresidue purified by flash chromatography on silicagel (EtOAc/MeOH/NH₄OH:90/10/1). After concentration of the desired fractions, the residue wascrystallised from diethyl ether to afford 0.120 g (yield 71%) of thetitle compound as a white amorphous solid.

C₃₅H₄₆N₆O MW=566.79

EXAMPLE 823-(4-Carbamimidoyl-piperazin-1-ylmethyl)-2-phenyl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide sesqui-p-toluenesulphonate

0.3 g (0.66 mmol) of2-phenyl-3-piperazin-1-ylmethyl-quinoline-4-carboxylic acid((S)-1-cyclohexyl-ethyl)amide (compound of Example 34), 0.313 g (0.94mmol) of benzotriazole-1-carboxamidinium p-toluenesulphonate (reagentdescribed in Synthetic Communications, 1995, 25 (8), 1173-1186), 0.167ml (0.94 mmol) of diisopropylethylamine were stirred for 3 days.Addition of diethyl ether led to the formation of a precipitate whichwas further triturated with ethyl ether. The white solid was purified bytwo successive flash chromatographies on silicagel, eluting first withCH₂Cl₂/MeOH: 90/10, then with CH₂Cl₂/MeOH/NH₄OH: 90/10/1. Concentrationof the desired fractions gave a solid which was triturated with diethylether to afford 0.225 g of the title compound as a salt ofp-toluenesulfonic acid. Analysis of the NMR spectra suggested theoccurrence of 1.6 equivalent of acid for one molecule of parent compound(in Table 2, the NMR refers to the parent compound).

C₃₀H₃₈N₆O.1.5C₇H₈O₃S MW=757.00

EXAMPLE 843-[4-(1-Methanesulfonylimino-1-pyrrolidin-1-yl-methyl)-piperazin-1-ylmethyl]-2-phenyl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide

0.46 g (0.76 mmol) of crude3-[4-(1-methanesulfonylimino-1-methylsulfanyl-methyl)-piperazin-1-ylmethyl]-2-phenyl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide (compound of Description 16) and 5ml of pyrrolidine were heated to reflux for 5 h. The excess ofpyrrolidine was removed in vacuo and the residue was purified by flashchromatography on silicagel (CH₂Cl₂/MeOH: 97/3). After concentration ofthe desired fractions, the residue was crystallised in di-isopropylether to afford 0.310 g (yield 65%) of the title compound as whitecrystals.

C₃₅H₄₆N₆O₃S MW=630.85

EXAMPLE 854-(4-{4-[4-((S)-2-Methyl-1-phenyl-propylcarbamoyl)-2-phenyl-quinolin-3-ylmethyl]-piperazin-1-yl}-4-oxo-butyricacid

200 mg (0.42 mmol) of2-phenyl-3-piperazin-1-ylmethylquinoline-4-carboxylic acid((S)-1-phenyl-propyl)-amide (compound of Description 13) were dissolvedin 5 ml acetone and 42 mg of succinic anhydride were added. The mixturewas then refluxed for 10 hours. After cooling the mixture was dilutedwith 50 ml of CH₂Cl₂, washed three times with 30 ml water, dried overMgSO₄, concentrated to dryness. The residue was purified by flashchromatography on silicagel (CH₂Cl₂/MeOH: 90/10) to afford 130 mg of thetitle compound as white crystals (yield 54%).

C₃₅H₃₈N₄O₄ MW=578.71

EXAMPLE 902-Phenyl-3-(4-sulfamoyl-piperazin-1-ylmethyl)-quinoline-4-carboxylicacid ((S)-1-phenyl-propyl)-amide

3.0 g (5.78 mmol) of crude2-phenyl-3-(4-sulfamoyl-piperazin-1-ylmethyl)-quinoline-4-carboxylicacid (compound of Description 25) were dissolved in 150 ml of 1:1mixture of CH₂Cl₂ and dry THF; 2.41 ml (17.34 mmol) of triethylamnine(TEA) and 4.38 g (11.56 mmol) ofO-benzotriazol-1-yl-N,N,N′,N′-tetramethyl-uroniumhexafluorophosphate(HBTU) were added and the reaction mixture was cooled at 0° C. 1.56 g(11.56 mmol) of (S)-1-phenyl-propylamine, dissolved in 20 ml of dryCH₂Cl₂, were added dropwise and the reaction mixture was stirred at roomtemperature for 24 h and at 50° C. for 4 h. The solvent was evaporatedin vacuo to dryness and the residue was taken up with EtOAc, washed withH₂O and 1 N NaOH, dried over Na₂SO₄ and evaporated to dryness. The crudematerial was purified by flash column chromatography on 230-400 meshsilica gel, utilising a mixture of EtOAc/hexane 8:2. After triturationwith iPr₂O, 1.05 g of the title compound were recovered as a pale yellowsolid.

C₃₀H₃₃N₅O₃S MW=543.69 IR: (KBr) 3270, 3060, 2967, 1959, 1644, 1537,1492, 1455, 1354, 1163, 949, 764, 702 cm⁻¹.

EXAMPLE 913-(4Dimethylsulfamoyl-piperazin-1-ylmethyl)-2-phenyl-quinoline4-carboxylic acid ((S)-1-phenyl-propyl)-amide

1.4 g (2.85 mmol) of crude3-(4-Dimethylsulfamoyl-piperazin-1-ylmethyl)-2-phenyl-quinoline-4-carboxylicacid (compound of Description 26) were dissolved in 100 ml of 1:1mixture of CH₂Cl₂ and dry THF; 1.19 ml (8.55 mmol) of triethylamine(TEA) and 2.16 g (5.70 mmol) ofO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluroniumhexafluorophosphate(HBTU) were added and the reaction mixture was cooled at 0° C. 0.77 g(5.70 mmol) of (S)-1-phenyl-propylamine, dissolved in 15 ml of dryCH₂Cl₂, were added dropwise and the reaction mixture was stirred at roomtemperature for 24 h and at 50° C. for 4 h. The solvent was evaporatedin vacuo to dryness and the residue was taken up with EtOAc and washedwith H₂O and 1 N NaOH, dried over Na₂SO₄ and evaporated to dryness toyield a crude material which was purified by flash column chromatographyon 230-400 mesh silica gel, utilising a mixture of EtOAc/hexane 8:2.After trituration with iPr₂O, 0.3 g of title compound were recovered asa white powder.

C₃₂H₃₇N₅O₃S MW=571.74 IR: (KBr) 3315, 3059, 2965, 2813, 1955, 1661,1638, 1533, 1491, 1455, 1349, 1152, 947, 748, 702 cm⁻¹.

TABLE I

Molecular Molecular Melting [a]_(D) ²⁰ Ex. R R₁ R₂ Formula Weight Point(° C.) (c = 0.5, MeOH) 1

H

C₃₆H₄₂N₄O.2HCl 619.76 261-263 −49.0 (c = 0.48) 2

H

C₃₇H₃₇N₃O 539.73 90-95 −47.1 3

H

C₃₆H₄₂N₄O.2HCl 619.68 176-179 +16.7 (c = 0.6) 4

H

C₃₂H₄₂N₄O.2HCl 571.64 180-183 +19.5 (c = 0.57) 5

H

C₃₇H₄₄N₄O.2HCl 633.71 168-171 +16.1 (c = 0.57) 6

H

C₃₅H₄₂N₄O 534.75 amorphous solid −46.5 7

H

C₃₆H₄₄N₄O 548.78 amorphous solid −42.5 8

H

C₃₄H₄₀N₄O 520.72 amorphous solid −45.7 9

H

C₃₇H₄₄N₄O 560.79 amorphous solid −38.9 10

H

C₃₆H₄₄N₄O 548.78 amorphous solid −45.8 11

H

C₄₀H₄₂N₄O₂ 610.81 100 (dec) — 12

H

C₃₉H₃₉N₅O₂ 609.78 242-245 −44.2 13

H

C₃₅H₄₆N₄O.2HCl 611.70 180-184 +6.9 14

H

C₃₆H₄₂N₄O.2HCl 619.68 182-185 −4.1 15

H

C₃₄H₄₀N₄O₃ 552.71 158-160 — 16

H

C₃₃H₃₈N₄O₂ 522.69 138-140 — 17

H

C₃₂H₄₂N₄O₂ 514.71 113-115 18

H

C₃₆H₄₂N₄O₂ 562.75 166-168 19

H

C₃₅H₄₀N₄O₂ 548.73 157-165 20

H

C₃₃H₄₄N₄O₃ 544.74 126-128 21

H

C₃₉H₄₂N₄O 582.79 amorphous solid 22

H

C₃₈H₄₆N₄O 574.81 amorphous solid 23

H

C₃₂H₃₄N₄O₂ 506.65 117-119 24

H

C₃₆H₄₀N₄O₂ 560.74 150-152 25

H

C₃₃H₄₂N₄O₂ 526.72 149-151 26

H

C₃₃H₃₈N₆O₅ 534.70 197-199 27

H

C₃₄H₃₄N₆O₅ 542.68 157-159 28

H

C₃₂H₃₆N₄O₂ 508.66 142-144 29

H

C₃₁H₄₀N₄O₂ 500.68  95-105 30

H

C₃₅H₄₀N₄O.2HCl 605.66 208-210 −1.37 (c = 0.55) 31

H

C₃₇H₃₆N₄O₂ 623.47 180-182 32

H

C₃₆H₄₃N₅O 561.77 amorphous solid 33

H

C₃₅H₄₇N₅O 553.79 amorphous solid 34

H

C₂₉H₃₆N₄O 456.63 amorphous solid 35

H

C₃₈H₅₁N₅O 593.85 amorphous solid 36

H

C₃₁H₃₈N₄O₂ 498.67 219-221 37

H

C₃₁H₄₀N₄O.2HCl 557.61 188-190 +16.0 (c = 0.2) 38

H

C₃₈H₃₇N₅O₂ 595.74 195-197 39

H

C₃₇H₄₁N₅O₂ 587.76 204-206 40

H

C₃₃H₃₈N₄O 506.69 amorphous solid 41

H

C₃₇H₅₅N₅O 585.87 amorphous solid 42

H

C₃₄H₄₄N₄O₂ 540.75 135-137 43

H

C₃₅H₄₆N₄O₂ 554.77 150-160 44

H

C₃₅H₄₆N₄O₂ 554.77 amorphous solid 45

H

C₃₆H₄₂N₄O₂ 562.74 amorphous solid 46

H

C₃₃H₄₃N₅O₂ 541.74 173-175 47

H

C₃₆H₄₉N₅O₂ 583.82 104-106 48

H

C₃₆H₄₈N₆O₂ 596.81 162-163 49

H

C₃₃H₃₆N₄O.2HCl 577.60 196-198 −54.4 (c = 0.21) 50

H

C₃₆H₄₈N₄O.2HCl 625.73 203-205 −5.2 (c = 0.35) 51

H

C₃₆H₄₇N₅O₃ 597.80 amorphous solid 52

H

C₃₄H₄₀N₆O₂ 564.73 178-210 53

H

C₃₄H₄₇N₆O 700.75 amorphous solid 54

H

C₂₉H₃₅N₃O₂ 457.61 178-180 55

H

C₃₁H₃₄N₄O 478.64  98-102 56

H

C₃₅H₃₅N₅O 541.69 125-126 57

H

C₃₂H₃₇N₃O₃ 511.66 amorphous solid 58

H

C₃₁H₄₁N₃O₃ 503.68 114-115 59

H

C₃₄H₃₉N₅O 533.72 152-154 60

H

C₃₂H₃₆N₄O 492.66 114-120 61

H

C₃₂H₃₉N₃O₃ 513.68 184-185 62

H

C₃₆H₄₃N₅O 561.77  85-100 63

H

C₃₄H₃₆N₄O₂ 532.68 129-131 64

H

C₃₃H₃₃N₅O₃ 547.66 amorphous solid 65

H

C₃₄H₃₉N₅O 533.71 amorphous solid 66

7-OMe, 8-Br

C₃₇H₄₃BrN₄O₂ 655.68 156-160 −30.3 (c = 0.53) 67

7-OMe

C₃₇H₄₄N₄O₂ 576.78 208-210 −0.31 (c = 0.2) 68

H

C₃₄H₃₈N₄O 518.70 amorphous solid 69

H

C₃₄H₄₄N₄O 524.75 amorphous solid 70

H

C₃₅H₃₉N₅O₂ 561.73 amorphous solid 71

H

C₃₃H₃₄N₄O₃ 534.66 amorphous solid 72

H

C₃₇H₄₃N₅O₃ 605.78 170-180 73

H

C₃₂H₃₉N₇O 537.71 175-180 74

H

C₃₂H₃₉N₅OS 541.76 174-176 75

H

C₃₁H₃₉N₅OS 529.75 204-206 76

H

C₃₅H₄₃N₇O 577.77 154-155 77

H

C₃₄H₃₇N₅O₂ 547.70 240-242 78

H

C₃₅H₄₆N₆O 566.79 amorphous solid 79

H

C₃₇H₄₄N₄O 560.78 114-113 80

H

C₃₈H₄₇N₅O₂ 605.82 120-125 81

H

C₃₅H₄₄N₆O₃ 596.77 164-165 82

H

C₃₀H₃₈N₆O 757.00 amorphous solid 83

H

C₃₃H₄₀N₄O₄ 556.70 208-209 84

H

C₃₅H₄₆N₆O₃S 630.85 130-140 85

H

C₃₅H₃₈N₄O₄ 578.71 173-175 86

H

C₃₉H₃₈N₄O₄ 626.75 189-191 87

H

C₃₇H₄₀N₄O₄ 604.75 209-211 88

7-OMe

C₃₆H₄₈N₄O₂ 641.72 139-144 (dec) +9.5 (c = 0.26) 89

7-OH, 8-Cl

C₃₆H₄₁ClN₄O₂ 670.12 209-216 (dec) +13.7 (c = 0.42) 90

H

C₃₀H₃₃N₅O₃S 543.69 133 (dec) −58.4 (c = 0.22) 91

H

C₃₂H₃₇N₅O₃S 571.74 107-111 (dec) −56.6 (c = 0.37) 92

H

C₃₁H₃₈N₄O₃ 514.67 188-195 93

H

C₃₆H₄₃N₅O 561.77 amorphous solid 94

H

C₃₆H₄₈N₄O 552.80 amorphous solid 95

7-OH

C₃₆H₄₂N₄O₂ 562.75 158-162 ″41.88 (c = 0.22)

TABLE 2 ¹H NMR data of compounds of Examples of Table 1 Exam- ple ¹H NMR(Solvent) δ ppm 1 δ(DMSOd₆): 0.96(3H); 1.00-1.20(5H); 1.50-1.73(5H);1.80 -2.00(2H); 2.00-2.10(5H); 2.16(4H); 3.50(2H); 5.10(1H); 7.29(1H);7.38(1H); 7.40-7.58(8H); 7.72(2H); 8.00(1H); 8.83(1H). 2 δ(DMSOd₆):0.99(3H); 1.20-1.35(2H); 1.43-1.51(2H); 1.70-1.80(2H); 1.80-2.05(2H);2.25(1H); 2.50(2H); 3.55(2H); 5.12(1H); 7.10(2H); 7.12(1H); 7.24(2H);7.29(1H); 7.39(2H); 7.42-7.61(8H); 7.73(2H); 8.01(1H); 8.83(1H). 3δ(DMSOd₆): 1.10-1.30(9H); 1.45-1.85(5H); 2.50-2.60(4H); 2.75-2.90(4H);3.68(2H); 4.00-4.10(1H); 4.19(2H); 7.39-7.59(11H); 7.69(1H); 7.89(1H);8.09(1H); 8.22(1H). 4 δ(DMSOd₆): 1.10-1.40(15H); 1.50-1.88(5H);2.50-2.60(8H); 3.25-3.35(1H); 3.79(2H); 4.00-4.10(1H); 7.45-7.80(7H);7.90(1H); 8.09(1H); 8.20(1H). 5 δ(DMSOd₆): 1.10-1.35(8H); 1.50-1.70(2H);1.70-1.88(4H); 2.58(4H); 2.90-3.35(8H); 3.73 and 3.80(2H);4.01-4.12(1H), 7.20-7.33(5H); 7.50-7.59(3H); 7.61-7.65(2H); 7.71(1H);7.85(1H); 7.91(1H); 8.17(1H); 8.47(1H). 6 δ(DMSOd₆): 0.85(6H); 0.97(3H);1.21(2H); 1.53(1H); 1.80-2.01(2H); 2.01-2.07(8H); 3.50(2H); 5.10(1H);7.29(1H); 7.38(2H); 7.41-7.58(8H); 7.73(2H); 8.00(1H); 8.81(1H). 7δ(DMSOd₆): 0.87(9H); 0.98(3H); 1.23(2H); 1.80-2.00(2H); 2.01-2.09(8H);2.14(2H); 3.50(2H); 5.10(1H); 7.28(1H); 7.38(2H); 7.41-7.59(8H);7.74(2H); 8.00(1H); 8.79(1H). 8 δ(DMSOd₆): 0.80(6H); 0.98(3H); 1.63(1H);1.80-2.00(4H); 2.00-2.09(8H); 3.50(2H); 5.10(1H); 7.28(1H); 7.38(2H);7.41-7.59(8H); 7.74(2H); 8.00(1H); 8.76(1H). 9 δ(DMSOd₆): 0.76-0.9(2H);0.98(3H); 1.10-1.40(4H); 1.55-1.70(5H); 1.80-2.07(12H); 3.50(2H);5.11(1H); 7.28(1H); 7.38(2H); 7.41-7.59(8H); 7.72(2H); 8.00(1H);8.79(1H). 10 δ(DMSOd₆): 0.80(6H); 0.98(3H); 1.18-1.32(6H);1.80-2.05(11H); 3.50(2H); 5.11(1H); 7.28(1H); 7.35(2H); 7.41-7.59(8H);7.74(2H); 8.00(1H); 8.79(1H). 11 δ(DMSOd₆): 0.96(3H); 1.65-1.99(9H);2.35-2.43(2H); 2.76(3H); −3.50(2H); 5.12(1H); 7.15-7.30(8H);7.42-7.59(8H); 7.72(2H); 8.01(1H); 8.81(1H). 12 δ(DMSOd₆): 0.98(3H);1.22-1.35(2H); 1.80-2.00(2H); 2.12-2.38(4H); 2.50-2.58(2H); 3.62(2H);4.51(2H); 5.18(1H); 6.80(3H); 7.23-7.32(3H); 7.38(2H); 7.41-7.62(8H);7.73(2H); 8.01(1H); 8.14(1H); 8.81(1H). 13 δ(DMSOd₆): 1.00-1.85(24H);2.50(8H); 3.30(1H); 3.50(2H); 4.00(1H); 7.40-7.55(5H); 7.65(1H);7.79(1H); 7.81(1H); 8.00(1H); 8.58(1H). 14 δ(DMSOd₆): 0.99(3H);1.40-2.05(14H); 2.40-2.50(1H); 2.70-2.89(4H); 3.50(2H); 5.09(1H);7.29(1H); 7.38(2H); 7.41-7.59(8H); 7.72(2H); 8.00(1H); 8.89(1H). 15δ(CDCl₃): 1.06(3H); 1.65-2.30(10H and 1Hexch with D2O); 2.39(2H);3.39-3.72(8H); 5.29(1H); 7.20-7.50(10Har and 1Hexch with D20);7.55(1Har); 7.72(1Har); 8.02(1Har); 7.13(1Har). 16 δ(CDCl₃): 1.04(3H);1.62-2.55(10H); 2.37(2H); 3.28(3H); 3.37(2H); 3.64(2H); 5.31(1H);7.18-7.50(10Har); 7.56(1Har); 7.72(1Har); 8.00-8.16(2Har); 8.98(1Hexchwith D2O). 17 δ(CDCl₃): 1.00-1.32(5H); 1.28(3H); 1.42(1H);1.52-1.95(5H); 2.03-2.58(10H); 3.30(3H); 3.43(2H); 3.77(2H); 4.26(1H);7.35-7.52(5Har); 7.62(1Har); 7.73(1Har); 8.12(2Har); 8.47(1Hexch withD20). 18 δ(CDCl₃): 1.04(3H); 0.70-1.35(2H); 1.40-2.61(14H and 1Hexchwith D20); 2.73(2H); 3.57(2H); 3.71(2H); 5.30(1H); 7.22-7.63(11Har);7.72(1Har); 8.02(1Har); 8.12(1Har); 8.52(1Hexch with D2O). 19 δ(CDCl₃):1.04(3H); 1.32-1.73(6H); 1.75-2.22(4H); 2.37(4H); 2.50(1H); 3.58(2H);3.67(4H); 5.32(1H); 7.20-7.62(11Har); 7.71(1Har); 8.02(1Har);8.11(1Har); 8.67(1Hexch with D2O). 20 δ(CDCl₃): 0.93-1.35(5H); 1.29(3H);1.45(1H); 1.57-2.67(15H and 1Hexch with D2O); 3.43-3.71(6H); 3.76(2H);4.25(1H); 7.32-7.50 (5Har); 7.48(1Har); 7.74(1Har); 7.60-7.90(1Hexchwith D2O); 8.08(1Har); 8.13(1Har). 21 δ(CDCl3): 0.65-1.07(2H); 0.96(3H);1.10-1.48(2H); 1.50-1.80(5H); 1.91(2H); 2.18(1H); 2.73(2H); 3.42(2H);3.70(1H); 3.85(1H); 5.22(1H); 7.12-7.60(16Har); 7.72(1Har); 8.02(1Har);8.12(1Har); 8.69(1Hexch with D2O). 22 δ(CDCl₃): 0.72-2.22(18H);1.28(3H); 2.01(3H); 2.83(2H); 3.48(2H); 3.75(1H); 3.95(1H); 4.21(1H);7.15-7.65(11Har and 1Hexch with D2O); 7.72(1Har); 8.06(1Har);8.14(1Har). 23 δ(CDCl₃): 1.03(3H); 1.52-2.25(6H); 1.93(3H); 2.93(2H);3.14(2H); 3.59(2H); 5.30(1H); 7.20-7.82(13Har); 7.97(1Hexch with D2O);8.12(1Har). 24 δ(CDCl₃): 0.95-1.37(5H); 1.28(3H); 1.45(1H);1.60-1.96(5H); 2.22(4H); 3.32(2H); 3.48(1H); 3.75(2H); 4.28(1H);6.90(1Hexch with D2O); 7.20-7.66(11Har); 7.74(1Har); 7.00(1Har);8.14(1Har). 25 δ(CDCl₃): 0.92-1.36(5H); 1.05(6H); 1.30(3H); 1.46(1H);1.53-1.95(5H); 2.19(4H); 2.67(1H); 3.27(2H); 3.39(2H); 3.73(2H);4.28(1H); 7.05(1Hexch with D2O); 3.37-7.54(5Har); 7.62(1Har);7.78(1Har); 8.03(1Har); 8.17(1Har). 26 δ(CDCl₃): 0.95-1.37(5H);1.31(3H); 1.62(1H); 1.56-1.98(5H); 2.26(4H); 3.61(4H); 3.80(2H);4.29(1H); 6.46(1Har); 7.33-7.56(5Har); 7.60(1Har); 7.76(1Har);7.83(1Hexch with D2O); 8.13(2Har); 8.25(2Har). 27 δ(CDCl₃): 1.05(3H);1.60(2H); 1.92-2.22(4H); 3.39(4H); 3.65(2H); 5.38(1H); 6.44(1Har);7.20-7.53(10Har); 7.58(1Har); 7.74(1Har); 8.07(1Har); 8.14(1Har);8.28(2Har); 8.43(1Hexch with D2O). 28 δ(CDCl₃): 1.03(3H); 1.73-2.30(10Hand 1Hexch with D2O); 2.41(2H); 3.54(2H); 3.63(2H); 5.29(1H);7.25-7.50(10Har); 7.55(1Har); 7.72(1Har); 8.03(1Har); 8.11(1Har);8.16(1Hexch with D2O). 29 δ(CDCl₃): 0.85-1.55(6H); 1.29(3H);1.56-2.12(7H); 2.26(4H); 2.35(2H); 2.46(2H); 3.01(1Hexch with D2O);3.55(2H); 3.76(2H); 4.26(1H); 7.35-7.52(5Har); 7.59(1Har); 7.74(1Har);7.92(1Hexch with D2O); 8.11(2Har). 30 δ(DMSO, 353K): 1.25(2H); 1.45(2H);1.55(3H); 1.65(6H); 2.72(4H); 3.00(5H); 3.50(2H); 5.32(1H);7.60-7.27(11Har); 7.75(2Har); 8.01(1Har); 8.90(1Hexch with D2O). 31δ(DMSOd₆) (80° C.): 0.98(3H); 1.92(2H); 2.23(4H); 3.23(4H); 3.80(2H);5.03(1H); 7.15-7.90(18har); 8.08(1Har); 9.15(1Hexch with D20). 32δ(CDCl₃): 1.03(3H); 1.29-2.30(17H); 2.24(3H); 2.48(2H); 3.64(2H);5.32(1H); 7.21-7.51(10Har); 7.58(1Har); 7.75(1Har); 8.13(2Har);9.00(1Hexch with D2O). 33 δ(CDCl₃): 0.98-2.55(26H); 1.28(3H); 2.25(3H);2.90(2H); 3.76(2H); 4.27(1H); 7.32-7.52(5Har); 7.59(1Har); 7.75(1Har);8.13(2Har); 8.46(1Hexch with D20). 34 δ(CDCl₃): 0.97-1.35(5H); 1.30(3H);1.42(1H); 1.60-1.98(5H); 2.22(4H and 1Hexch with D2O); 2.70(4H);3.72(2H); 4.27(1H); 7.35-7.52(5Har); 7.58(1Har); 7.75(1Har); 7.88(1Hexchwith D2O); 8.08(1Har); 8.13(1 Har). 35 δ(CDCl₃): 0.78(12H); 1.01(3H);1.92-2.42(18H); 3.60-3.95(2H); 5.28(1H); 7.22-7.56(11Har); 7.69(1Har);7.82(1Har); 8.10(1Har); 8.49(1Hexch with D2O). 36 δ(CDCl₃):0.70-2.03(20H); 1.42(3H); 3.43-3.64(3H); 7.37(1Hexch with D2O);7.42-7.60(5Har); 7.66(1Har); 7.79(1Har); 7.94(1Har); 7.98(1Hexch withD2O); 8.03(1Har); 8.17(1Hexch with D20). 37 δ(DMSO): 0.92(3H);1.30-1.10(9H); 1.85-1.60(5H); 2.30-2.10(10H); 3.58(2H); 4.04(1H);7.51-7.41(3Har); 7.57(2Har); 7.62(1Har); 7.76(1Har); 7.87(1Har);8.01(1Har); 8.30(1Hexch with D2O). 38 δ(CDCl₃): 1.10(3H); 1.32-2.38(9H);2.61(1H); 3.70(2H); 4.07(1H); 5.39(1H); 6.87-7.10(4Har);7.22-7.64(11Har); 7.73(1Har); 8.04(1Har); 8.15(1Har); 8.30(1Hexch withD20); 8.98(1Hexch with D20). 39 δ(CDCl₃): 1.02-1.43(5H); 1.34(3H);1.45-2.36(12H); 2.26(1H); 2.38(1H); 3.82(2H); 4.19(1H); 4.37(1H);7.02(4Har); 7.38-7.86(7Har and 1Hexch with D2O); 8.09(1Har); 8.16(1Har);8.91(1hexch with D2O). 40 δ(DMSOd₆) (80° C.): 0.99(3H); 1.47(2H);1.72(2H); 1.90(2H); 2.03(3H); 2.64(3H); 2.55-3.00(3H); 3.28(2H);4.05(2H); 5.10(1H); 7.25-7.95(13Har); 8.10(1Har); 9.49(1Hexch with D2O).41 δ(CDCl₃): 0.95-2.95(26H); 2.64-3.32(16H); 3.95(1H); 4.11(1H);4.38(1H); 6.82(1Hexch with D2O); 7.42-7.20(6Har); 7.61-7.87(2Har);8.18(1Har). 42 δ(CDCl₃): 0.92-1.94(17H); 1.29(3H); 2.04(1H); 2.43(4H);2.53(1H); 2.79(1H); 3.52-3.82(6H); 4.28(1H); 7.34-7.55(5Har);7.60(1Har); 7.72(1Har); 8.00-8.30(2Har and 1Hexch with D2O). 43δ(CDCl₃): 0.95-2.07(23H and 1Hexch with D2O); 1.28(3H); 2.13-2.45(2H);2.53(1H); 2.77(2H); 3.68(3H); 4.25(1H); 7.33-7.67(6Har); 7.75(1Har);8.10(2Har); 7.70-8.20(1Hexch with D2O). 44 δ(CDCl₃): 0.94-2.02(27H);2.30-2.61(2H); 2.98-3.40(4H); 3.73(2H); 4.25(1H); 7.32-7.52(5Har);7.56(1Har); 7.72(1Har); 7.60-7.80(1Hexch with D2O); 8.06(1Har);8.13(1Har). 45 δ(CDCl₃): 0.92-1.15(9H); 1.20-1.70(6H); 1.80-2.12(3H);2.22(1H); 2.40(1H); 3.08(2H); 3.23(2H); 3.50(1H); 3.15(1H); 5.31(1H);7.21-7.62(11Har); 7.20(1Har); 7.33-8.22(2Har and 1Hexch with D2O). 46δ(CDCl₃): 1.00-1.49(5H); 1.28(3H); 1.47(1H); 1.60-1.97(5H);2.09-2.47(4H); 2.21(6H); 3.01(2H); 3.36(4H); 3.73(2H); 4.27(1H);7.06(1Hexch with D20); 7.38-7.56(5Har); 7.60(1Har); 7.75(1Har);8.02(1Har); 8.16(1Har). 47 δ(CDCl₃): 0.85-1.38(5H); 1.03(6H); 1.28(3H);1.44(1H); 1.60-1.95(5H); 2.19(4H); 2.35-2.67(6H); 2.78(2H); 3.24(2H);3.38(2H); 3.74(2H); 4.48(1H); 7.07(1Hexch with D2O); 7.34-7.59(5Har);7.63(1Har); 7.78(1Har); 8.02(1Har); 8.14(1Har). 48 δ(DMSOd₆):0.93-1.35(5H); 1.16(3H); 1.48(1H); 1.58-1.92(5H); 1.98-2.29(4H);2.24(3H); 2.40(8H); 3.07(2H); 2.96-3.65(4H); 3.58(2H); 4.02(1H);7.40-7.91(8Har); 8.04(1Har); 8.60(1Hexch with D2O). 49 δ(DMSO):0.95(3H); 1.10(2H); 2.00-1.50(9H); 2.22(1H); 2.41(1H); 2.59(1H);2.81(1H); 3.55(2H); 5.10(1H); 7.59-7.25(11Har); 7.75(2Har); 8.01(1Har);8.83(1Hexch with D2O). 50 δ(DMSO + TFA 353 K): 1.00(3H); 1.30-1.10(6H);1.89-1.50(17H); 2.02(2H); 3.20-2.80(7H); 4.00(1H); 4.20(2H);7.61-7.51(3Har); 7.65(3Har); 7.88(1Har); 7.98(1Har); 8.10(1Har);8.65(1Hexch with D2O). 51 δ(DMSOd₆): 0.90-1.35(5H); 1.14(3H); 1.46(1H);1.55-1.90(5H); 2.03(4H); 2.22-2.52(8H); 3.15(4H); 3.42-3.70(6H);3.99(1H); 7.32-8.12(6Har); 8.53(1Hexch with D2O). 52 δ(DMSOd₆):0.95-1.35(5H); 1.20(3H); 1.46(1H); 1.58-1.88(5H); 2.05(2H); 2.87(4H);3.03-3.30(4H); 3.60(2H); 4.01(1H); 6.86(1H); 7.30-8.10(10H and 1Hexchwith D2O); 8.54(1Hexch with D2O). 53 δ(DMSOd₆): 0.95-1.32(5H); 1.17(3H);1.47(1H); 1.55-1.95(5H); 2.26(4H); 2.82(12H); 3.03(4H); 3.62(2H);4.01(1H); 7.38-7.88(8Har); 8.03(1Har); 8.54(1Hexch with D2O). 54δ(DMSOd₆): 0.95-1.37(5H); 1.17(3H); 1.46(1H); 1.57-1.92(5H); 2.08(4H);3.30(4H); 3.55(2H); 4.02(1H); 7.32-7.91(8Har); 8.02(1Har); 8.53(1Hexchwith D2O). 55 δ(CDCl₃): 0.60-2.25(9H and 2Hexch with D2O); 1.06(3H);2.41(2H); 3.57(2H); 5.30(1H); 7.15-7.65(10Har); 7.72(1Har); 8.02(1Har);8.14(2Har); 8.80(1Hexch with D2O). 56 δ(CDCl₃): 1.03(3H); 1.75-2.28(6H);3.09(4H); 3.65(2H); 5.33(1H); 6.45(1Har); 6.58(1Har); 7.18-7.65(12Har);7.75(1Har); 8.93-8.20(3Har); 8.39(1Hexch with D2O). 57 δ(CDCl₃):0.97(3H); 2.02(2H); 2.33(4H); 2.94(6H); 3.03(4H); 3.88(2H); 5.23(1H);7.19-7.60(10Har and 1Hexch with D2O); 7.68(1Har); 7.86(1Har);8.02(1har); 8.22(1Har). 58 δ(CDCl₃): 0.98-1.42(5H); 1.26(3H);1.43-1.98(6H); 2.53(4H); 3.00(6H); 2.90-3.32(4H); 3.95(2H); 4.22(1H);7.35-7.78(7Har and 1Hexch with D2O); 7.98(1Har); 8.10(1Har). 59δ(CDCl₃): 1.30(3H); 0.95-2.02(11H); 2.31(4H); 3.32(4H); 3.80(2H);4.28(1H); 6.48-6.68(2Har); 7.35-7.67(7Har); 7.73(1Har); 7.65-7.69(1Hexchwith D20); 8.02-8.22(3Har). 60 δ(CDCl₃): 0.77(3H); 0.85(3H); 1.02(3H);1.70-2.58(8H); 3.59(2H); 2.78(1H); 7.15-7.65(11Har and 1Hexch with D2O);7.75(1Har); 8.05(1Har); 8.14(1Har); 8.58(1Hexch with D2O). 61 δ(CDCl₃):0.95-2.00(15H); 1.29(3H); 2.28(4H); 3.77(2H); 3.87(4H); 4.23(1H);7.35-7.55(5Har); 7.60(1Har); 7.75(1Har); 7.95-8.25(2Har and 1Hexch withD2O). 62 δ(CDCl₃): 0.70-1.70(6H); 1.04(3H); 1.82-2.22(5H); 2.28(3H);2.35-2.65(8H); 3.57(2H); 5.32(1H); 7.20-7.64(11Har); 7.73(1Har);8.03(1Har); 8.13(1Har); 8.72(1Hexch with D2O). 63 δ(DMSOd₆): 0.95(3H);0.94-1.45(4H); 1.50-2.25(6H); 2.65-3.02(4H); 3.30(2H); 5.06(1H);7.20-8.00(13Har and 1Hexch with D2O); 8.02(1Har); 9.14(1Hexch with D2O).64 δ(CDCl₃): 1.02(3H); 1.10-1.88(6H); 1.90-2.28(3H); 2.45(1H); 3.59(2H);5.30(1H); 5.91(1Hexch with D2O); 7.18-7.62(11Har and 2Hexch with D2O);7.72(1Har); 795(1har); 8.13(1Har). 65 δ(CDCl₃): 1.29-2.22(15H);2.27(3H); 2.88(2H); 3.66(2H); 4.74(2H); 7.22-7.52(10Har); 7.59(1Har);7.77(1Har); 8.12(1Har); 8.22(1Har); 9.64(1Hexch with D2O). 66 δ(DMSO 343k): 0.95(3H); 1.08(2H); 1.65-1.25(11H); 1.88-1.80(2H); 2.50-2.25(6H);3.41(2H); 3.92(3H); 5.09(1H); 7.60-7.15(13Har); 8.90(1Hexch with D2O).67 δ(DMSO): 0.95(3H); 1.08(2H); 1.65-1.25(11H); 2.00-1.80(2H);2.50-2.25(6H); 3.49(2H); 4.00(3H); 5.09(1H); 7.71-7.25(12Har);8.90(1Hexch with D2O). 68 δ(DMSOd₆): 0.94(3H); 1.15-2.45(14H); 2.11(3H);3.60(2H); 5.05(1H); 7.15-7.59(13Har); 8.02(1Har); 9.16(1Hexch with D2O)69 δ(CDCl₃): 1.05-2.23(22H); 1.34(3H); 2.24-2.63(5H); 2.28(1H);3.69(2H); 4.24(1H); 7.35-7.65(6Har); 7.73(1Har); 8.12(2Har); 8.47(1Hexchwith D2O). 70 δ(CDCl₃): 0.80-1.44(4H); 1.04(3H); 1.53-2.29(7H);2.50(1H); 2.89(2H); 3.20(2H); 3.63(2H); 4.02(1H); 4.49(1Hexch with D2O);5.29(1H); 7.18-7.55(10Har); 7.56(1Har); 7.74(1Har); 8.10(2Har);8.74(1Hexch with D2O). 71 δ(CDCl₃): 1.01(3H); 1.26(2H); 1.41-1.68(2H);1.35-2.30(6H); 3.06(2H); 3.62(2H); 4.99(1Hexch with D2O); 5.26(1H);7.22-7.50(10Har); 7.57(1Har); 7.73(1Har); 7.41(1Hexch with D2O);8.02(1Har); 8.12(1Har). 72 δ(CDCl₃): 0.98-1.39(5H); 1.28(3H); 1.49(1H);1.63-1.98(9H); 2.30(4H); 3.47(4H); 3.64(4H); 3.71(2H); 4.24(1H);6.54(1Hexch with D2O); 7.35-7.53(5Har); 7.60(1Har); 7.73(1Har);7.94(1Har); 8.12(1Har). 73 δ(CDCl₃): 0.99-1.37(5H); 1.27(3H); 1.48(1H);1.63-1.90(5H); 2.23(4H); 2.93(3H); 3.19(4H); 3.70(2H); 4.24(1H);4.84(1Hexch with D20); 6.55(1Hexch with D2O); 7.36-7.52(5Har);7.59(1Har); 7.73(1Har); 7.94(1Har); 8.13(1Har). 74 δ(CDCl₃):0.98-1.37(5H); 1.26(3H); 1.42(1H); 1.54-1.93(5H); 2.20(4H); 3.21(4H);3.25(2H); 3.75(2H); 3.95(2H); 4.26(1H); 7.32-7.67(5Har and 1Hexch withD2O); 7.58(1Har); 7.73(1Har); 8.03(1Har); 8.13(1Har). 75 δ(CDCl₃):0.96-1.32(5H); 1.25(3H); 1.43(1H); 1.63-1.91(5H); 2.22(4H); 3.07(3H);3.54(4H); 3.71(2H); 4.25(1H); 5.58(1Hexch with D2O); 6.90(1Hexch withD2O); 7.38-7.52(5Har); 7.58(1Har); 7.72(1Har); 8.92(1Har); 8.10(1Har).76 δ(CDCl₃): 1.00-1.35(5H); 1.28(3H); 1.45(1H); 1.63-1.93(9H); 2.29(4H);3.18(4H); 3.33(4H); 3.73(2H); 4.22(1H); 6.65(1Hexch with D2O);7.42-7.52(5Har); 7.61(1Har); 7.71(1Har); 7.76(1Har); 8.13(1Har). 77δ(DMSOd₆): 0.98(3H); 1.03-2.00(5H); 1.81(2H); 2.05-2.62(2H);2.95-3.72(8H); 5.08(1H); 6.16(1Hexch with D2O); 7.17-7.70(12Har);7.77(1Har); 8.02(1Har); 9.12(1Hexch with D2O). 78 δ(CDCl₃):0.96-1.40(5H); 1.30(3H); 1.51(1H); 1.62-1.87(5H); 1.88-2.03(4H);2.20-2.42(4H); 2.85, 2.87(3H, 2forms); 2.98-3.15(4H); 3.38-3.62(4H);3.75(2H); 4.23(1H); 6.27(1Hexch with D2O); 7.38-7.81(7Har); 7.92(1Har);8.15(1Har). 79 δ(CDCl₃): 0.93(3H); 1.19(3H); 1.05-1.65(8H);1.68-1.83(4H); 1.90-2.55(8H); 3.52(2H); 5.14(1H); 7.33-7.60(11Har);7.71(1Har); 8.00(1Har); 8.11(1Har); 8.47(1Hexch with D2O). 80 δ(CDCl₃):0.94(3H); 1.08(6H); 1.17(3H); 1.86(4H); 2.23(1H); 2.46(2H); 2.63(4H);2.83(2H); 3.02(2H); 3.17(2H); 3.53(2H); 5.14(1H); 7.29-7.55(11Har and1Hexch with D2O); 7.73(1Har); 7.91(1Har); 8.13(1Har) 81 δ(CDCl₃):0.99-1.38(5H); 1.30(3H); 1.49(1H); 1.57-1.99(9H); 2.18-2.38(4H);2.98-3.15(4H); 3.22-3.37(4H); 3.75(2H); 4.25(1H); 6.28(1H); 6.63(1Hexchwith D2O); 7.37-7.55(5Har); 7.60(1Har); 7.74(1Har); 7.98(1Har);8.14(1Har). 82 δ(DMSOd₆): 0.951-1.32(8H); 1.32(1H); 1.57-1.86(5H);2.15-2.36(4H); 2.29(3H); 2.77(2H); 3.11(2H); 3.60(2H); 4.00(1H);7.11(2Har); 7.27(2Hexch with D2O); 7.48(2Har); 7.49-7.61(5Har);7.62(1Har); 7.88(2Har); 8.03(1Har); 8.57(3Hexch with D2O). 83 δ(CDCl₃):0.98-1.36(5H); 1.28(3H); 1.45(1H); 1.60-1.95(5H); 2.08-2.27(4H);2.47-2.66(4H); 3.00(1Hexch with D2O); 3.23(2H); 3.37(2H); 3.73(2H);4.26(1H); 6.85(1Hexch with D2O); 7.39-7.54(5Har); 7.60(1Har);7.75(1Har); 7.99(1Har); 8.15(1Har). 84 δ(CDCl₃): 1.00-1.39(5H);1.29(3H); 1.47(1H); 1.68-1.97(9H); 2.18-2.36(4H); 2.92(3H);3.16-3.49(8H); 3.74(2H); 4.25(1H); 6.93(1Hexch with D2O);7.38-7.53(5Har); 7.59(1Har); 7.74(1Har); 8.00(1Har); 8.13(1Har). 85δ(CDCl₃): 0.93(3H); 1.17(3H); 1.71-2.03(4H); 2.21(1H); 2.40-2.66(4H);300-3.50(1Hexch with D2O); 3.01(2H); 3.18(2H); 3.51(2H); 5.13(1H);7.01(1Hexch with D2O); 7.25-7.52(10Har); 7.55(1Har); 7.73(1Har);7.89(1Har); 8.14(1Har). 86 δ(CD₃COD): 0.84(3H); 1.19(3H); 1.36-2.41(5H);2.65(2H); 2.80-3.70(2H); 3.24(1H); 3.45(1H); 4.96(1H); 7.00-8.15(18Harand 2Hexch with D2O). 87 δ(CD₃COD): 1.01-1.96(11H); 1.25(3H);1.97-2.53(4H); 2.93(2H); 3.20-3.80(2H); 3.67(2H); 4.10(1H); 7.17(1Har);7.37-8.14(12H and 2Hexch with D2O). 88 δ(DMSO): 1.40-1.08(5H); 1.50(2H);1.90-1.63(21H); 3.10-2.50(5H); 4.54(2H); 3.91(3H); 4.00(1H); 7.28(1Har);7.41(1Har); 7.57-7.42(5Har); 7.74(1Har); 8.29(1Hexch with D2O). 89δ(DMSO): 0.95(3H); 1.08(2H); 1.60-1.30(11H); 1.96-1.75(3H);2.50-2.25(6H); 3.30(2H); 5.00(1H); 6.80(1Har); 7.42-7.12(9Har);7.54(2Har); 8.65(1Hexch with D2O). 90 δ(DMSO 343K): 0.97(3H);2.10-1.80(6H); 2.69(4H); 3.51(2H); 5.09(1H); 6.40(2Hexch with D2O);7.55-7.21(11Har); 7.72(2Har); 8.00(1Har); 8.89(1Hexch with D2O). 91δ(DMSO 343K): 0.98(3H); 2.10-1.80(6H); 2.70(6H); 2.79(4H); 3.55(2H);5.10(1H); 7.57-7.21(11Har); 7.75(2Har); 8.00(1Har); 8.89(1Hexch withD2O); 92 δ(DMSOd₆): 0.88-1.35(5H); 1.16(3H); 1.45(1H); 1.53-1.93(5H);2.16(4H); 2.30(4H); 2.90(2H); 3.56(2H and 1Hexch with D2O); 4.02(1H);7.22-7.90(8Har); 8.03(1Har); 8.55(1Hexch with D2O)ppm. 93 δ(CDCl₃):0.94(3H); 0.98-1.34(2H); 1.19(3H); 1.36-1.67(2H); 1.70-2.56(6H and1Hexch with D20); 2.43(4H); 2.88(4H); 2.52(2H); 5.15(1H);7.22-7.60(11Har); 7.71(1Har); 7.99(1Har); 8.11(1Har); 8.35(1Hexch withD2O). 94 δ(CDCl3): 1.13-2.66(31H); 2.81(1H); 3.64(1H); 3.74(1H);4.35(1H); 7.38-7.53(5Har); 7.58(1Har); 7.73(1Har); 8.13(1Har);7.70-8.50(1Hexch with D2O) 95 δ(DMSOd₆): 0.95(3H); 1.09(2H);1.34-1.50(8H); 1.50-1.65(2H); 1.80-1.98(3H); 2.35(4H); 2.42(2H);3.40(2H); 5.09(1H); 7.09(1Har); 7.22(1Har); 7.25-7.55(11Har);8.88(1Hexch with D2O); 9.98(1Hexch with D2O).

TABLE 3 Chemical names of parent compounds of Examples of Table 1 (namesgenerated by Beilstein's Autonom) Exam- ple Chemical name 13-(4-Cyclohexyl-piperazin-1-ylmethyl)-2-phenyl-quinoline-4- carboxylicacid ((S)-1-phenyl-propyl)-amide 22-Phenyl-3-(4-phenyl-piperidin-1-ylmethyl)-quinoline-4- carboxylic acid((S)-1-phenyl-propyl)-amide 33-(4-Benzyl-piperazin-1-ylmethyl)-2-phenyl-quinoline-4- carboxylic acid((S)-1-cyclohexyl-ethyl)-amide 43-(4-Isopropyl-piperazin-1-ylmethyl)-2-phenyl-quinoline-4- carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide 53-(4-Phenethyl-piperazin-1-ylmethyl)-2-phenyl-quinoline-4- carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide 63-[4-(3-Methyl-butyl)-piperazin-1-ylmethyl]-2-phenyl-quinoline-4-carboxylic acid ((S)-1-phenyl-propyl)-amide 73-[4-(3,3-Dimethyl-butyl)-piperazin-1-ylmethyl]-2-phenyl-quinoline-4-carboxylic acid ((S)-1-phenyl-propyl)-amide 83-(4-Isobutyl-piperazin-1-ylmethyl)-2-phenyl-quinoline-4- carboxylicacid ((S)-1-phenyl-propyl)-amide 93-(4-Cyclohexylmethyl-piperazin-1-ylmethyl)-2-phenyl-quinoline-4-carboxylic acid ((S)-1-phenyl-propyl)-amide 103-[4-(2-Ethyl-butyl)-piperazin-1-ylmethyl]-2-phenyl-quinoline-4-carboxylic acid ((S)-1-phenyl-propyl)-amide 113-[(Acetyl-methyl-amino)-phenyl-piperidin-1-ylmethyl]-2-phenyl-quinoline-4-carboxylic acid ((S)-1-phenyl-propyl)-amide 123-(4-Oxo-1-phenyl-1,3,8-triaza-spiro[4.5]dec-8-ylmethyl)-2-phenyl-quinoline-4-carboxylic acid ((S)-1-phenyl-propyl)-amide 133-[1,4′]Bipiperidinyl-1′-ylmethyl-2-phenyl-quinoline- 4-carboxylic acid((S)-1-cyclohexyl-ethyl)-amide 143-[1,4′]Bipiperidinyl-1′-ylmethyl-2-phenyl-quinoline- 4-carboxylic acid((S)-1-phenyl-propyl)-amide 153-{4-[2-(2-Hydroxy-ethoxy)-ethyl]-piperazin-1-ylmethyl}-2-phenyl-quinoline-4-carboxylic acid ((S)-1-phenyl-propyl)-amide 163-[4-(2-Methoxy-ethyl)-piperazin-1-ylmehyl]-2-phenyl-quinoline-4-carboxylic acid ((S)-1-phenyl-propyl)-amide 173-[4-(2-Methoxy-ethyl)-piperazin-1-ylmethyl]-2-phenyl-quinoline-4-carboxylic acid ((S)-1-cyclohexyl-ethyl)-amide 183-(4-Hydroxy-[1,4′]bipiperidinyl-1′-ylmethyl)-2-phenyl-quinoline-4-carboxylic acid ((S)-1-phenyl-propyl)-amide 193-(4-Morpholin-4-yl-piperidin-1-ylmethyl)-2-phenyl-quinoline-4-carboxylic acid ((S)-1-phenyl-propyl)-amide 203-{4-[2-(2-Hydroxy-ethoxy)-ethyl]-piperazin-1-ylmethyl}-2-phenyl-quinoline-4-carboxylic acid((S)-1-cyclohexyl-ethyl)-amide 213-{[(1-Benzyl-piperidin-4-yl)-methyl-amino]-methyl}-2-phenyl-quinoline-4-carboxylic acid ((S)-1-phenyl-propyl)-amide 223-{[(1-Benzyl-piperidin-4-yl)-methyl-amino]-methyl}-2-phenyl-quinoline-4-carboxylic acid ((S)-1-cyclohexyl-ethyl)-amide 233-(4-Acetyl-piperazin-1-ylmethyl)-2-phenyl-quinoline-4- carboxylic acid((S)-1-phenyl-propyl)-amide 242-Phenyl-3-[4-(1-phenyl-methanoyl)-piperazin-1-ylmethyl]-quinoline-4-carboxylic acid ((S)-1-cyclohexyl-ethyl)-amide 253-[4-(2-Methyl-propanoyl)-piperazin-1-ylmethyl]-2-phenyl-quinoline-4-carboxylic acid ((S)-1-cyclohexyl-ethyl)-amide 262-Phenyl-3-(4-pyrimidin-2-yl-piperazin-1-ylmethyl)-quinoline-4-carboxylic acid ((S)-1-cyclohexyl-ethyl)-amide 272-Phenyl-3-(4-pyrimidin-2-yl-piperazin-1-ylmethyl)-quinoline-4-carboxylic acid ((S)-1-phenyl-propyl)-amide 283-[4-(2-Hydroxy-ethyl)-piperazin-1-ylmethyl]-2-phenyl-quinoline-4-carboxylic acid ((S)-1-phenyl-propyl)-amide 293-[4-(2-Hydroxy-ethyl)-piperazin-1-ylmethyl]-2-phenyl-quinoline-4-carboxylic acid ((S)-1-cyclohexyl-ethyl)-amide 303-[1,4′]Bipiperidinyl-1′-ylmethyl-2-phenyl-quinoline-4- carboxylic acid((S)-1-phenyl-ethyl)-amide 312-Phenyl-3-[4-(1-phenyl-methanoyl)-piperazin-1-ylmethyl]-quinoline-4-carboxylic acid ((S)-1-phenyl-propyl)-amide 323-[4-(1-Methyl-piperidin-4-yl)-piperazin-1-ylmethyl]-2-phenyl-quinoline-4-carboxylic acid ((S)-1-phenyl-propyl)-amide 333-[4-(1-Methyl-piperidin-4-yl)-piperazin-1-ylmethyl]-2-phenyl-quinoline-4-carboxylic acid ((S)-1-cyclohexyl-ethyl)-amide 342-Phenyl-3-piperazin-1-ylmethyl-quinoline-4-carboxylic acid((S)-1-cyclohexyl-ethyl)-amide 353-{[Bis-(2-diethylamino-ethyl)-amino]-methyl}-2-phenyl-quinoline-4-carboxylic acid ((S)-1-phenyl-propyl)-amide 363-(4-Carbamoyl-piperidin-1-ylmethyl)-2-phenyl-quinoline-4- carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide 373-(4-Ethyl-piperazin-1-ylmethyl)-2-phenyl-quinoline-4- carboxylic acid((S)-1-cyclohexyl-ethyl)-amide 383-[4-(2-Oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-ylmethyl]-2-phenyl-quinoline-4-carboxylic acid((S)-1-phenyl-propyl)-amide 393-[4-(2-Oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-ylmethyl]-2-phenyl-quinoline-4-carboxylic acid((S)-1-cyclohexyl-ethyl)-amide 403-{[Methyl-(1-methyl-piperidin-4-yl)-amino]-methyl}-2-phenyl-quinoline-4-carboxylic acid ((S)-1-phenyl-propyl)-amide 413-{[Bis-(2-diethylamino-ethyl)-amino]-methyl}-2-phenyl-quinoline-4-carboxylic acid ((S)-1-cyclohexyl-ethyl)-amide 423-(4-Morpholin-4-yl-piperidin-1-ylmethyl)-2-phenyl-quinoline-4-carboxylic acid ((S)-1-cyclohexyl-ethyl)-amide 433-(4-Hydroxy-[1,4′]bipiperidinyl-1′-ylmethyl)-2-phenyl-quinoline-4-carboxylic acid ((S)-1-cyclohexyl-ethyl)-amide 443-(3-Diethylcarbamoyl-piperidin-1-ylmethyl)-2-phenyl-quinoline-4-carboxylic acid ((S)-1-cyclohexyl-ethyl)-amide 453-(3-Diethylcarbamoyl-piperidin-1-ylmethyl)-2-phenyl-quinoline-4-carboxylic acid ((S)-1-phenyl-propyl)-amide 463-[4-(2-Dimethylamino-ethanoyl)-piperazin-1-ylmethyl]-2-phenyl-quinoline-4-carboxylic acid ((S)-1-cyclohexyl-ethyl)-amide 473-[4-(3-Diethylamino-propanoyl)-piperazin-1-ylmethyl]-2-phenyl-quinoline-4-carboxylic acid ((S)-1-cyclohexyl-ethyl)-amide 483-{4-[2-(4-Methyl-piperazin-1-yl)-ethanoyl]-piperazin-1-ylmethyl}-2-phenyl-quinoline-4-carboxylic acid((S)-1-cyclohexyl-ethyl)-amide 493-(Hexahydro-pyrrolo[1,2-a]pyrazin-2-ylmethyl)-2-phenyl-quinoline-4-carboxylic acid ((S)-1-phenyl-propyl)-amide 503-[1,4′]Bipiperidinyl-1′-ylmethyl-2-phenyl- quinoline-4-carboxylic acid51 3-[4-(3-Morpholin-4-yl-propanoyl)-piperazin-1-ylmethyl]-2-phenyl-quinoline-4-carboxylic acid ((S)-1-cyclohexyl-ethyl)-amide 523-[4-(2-1H-Imidazol-4-yl-ethanoyl)-piperazin-1-ylmethyl]-2-phenyl-quinoline-4-carboxylic acid ((S)-1-cyclohexyl-ethyl)-amide 53({4-[4-((S)-1-Cyclohexyl-ethylcarbamoyl)-2-phenyl-quinolin-3-ylmethyl]-piperazin-1-yl}-dimethylamino-methylene)-dimethyl-ammonium 543-Morpholin-4-ylmethyl-2-phenyl-quinoline-4-carboxylic acid((S)-1-cyclohexyl-ethyl)-amide 553-(4-Amino-piperidin-1-ylmethyl)-2-phenyl-quinoline-4- carboxylic acid((S)-1-phenyl-propyl)-amide 562-Phenyl-3-(4-pyridin-2-yl-piperazin-1-ylmethyl)-quinoline-4- carboxylicacid ((S)-1-phenyl-propyl)-amide 573-{[Bis-(2-methoxy-ethyl)-amino]-methyl}-2-phenyl-quinoline-4-carboxylic acid ((S)-1-phenyl-propyl)-amide 583-{[Bis-(2-methoxy-ethyl)-amino]-methyl}-2-phenyl-quinoline-4-carboxylic acid ((S)-1-cyclohexyl-ethyl)-amide 592-Phenyl-3-(4-pyridin-2-yl-piperazin-1-ylmethyl)-quinoline-4- carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide 603-((3R,5S)-3,5-Dimethyl-piperazin-1-ylmethyl)-2-phenyl-quinoline-4-carboxylic acid ((S)-1-phenyl-propyl)-amide 613-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-ylmethyl)-2-phenyl-quinoline-4-carboxylic acid ((S)-1-cyclohexyl-ethyl)-amide 623-[4-(4-Methyl-piperazin-1-yl)-piperidin-1-ylmethyl]-2-phenyl-quinoline-4-carboxylic acid ((S)-1-phenyl-propyl)-amide 633-(3-Oxo-2,8-diaza-spiro[4.5]dec-8-ylmethyl)-2-phenyl-quinoline-4-carboxylic acid ((S)-1-phenyl-propyl)-amide 643-(2,4-Dioxo-1,3,8-triaza-spiro[4.5]dec-8-ylmethyl)-2-phenyl-quinoline-4-carboxylic acid ((S)-1-phenyl-propyl)-amide 653-[4-(1-Methyl-piperidin-4-yl)-piperazin-1-ylmethyl]-2-phenyl-quinoline-4-carboxylic acid benzylamide 663-[1,4′]Bipiperidinyl-1′-ylmethyl-8-bromo-7-methoxy-2-phenyl-quinoline-4-carboxylic acid ((S)-1-phenyl-propyl)-amide67 3-[1,4′]Bipiperidinyl-1′-ylmethyl-7-methoxy-2-phenyl-quinoline-4-carboxylic acid ((S)-1-phenyl-propyl)-amide 683-(7-Methyl-2,7-diaza-spiro[4.4]non-2-ylmethyl)-2-phenyl-quinoline-4-carboxylic acid ((S)-1-phenyl-propyl)-amide 693-[1,4′]Bipiperidinyl-1′-ylmethyl-2-phenyl- quinoline-4-carboxylic acid((S)-1-cyclopentyl-ethyl)-amide 703-[4-(2-Oxo-tetrahydro-pyrimidin-1-yl)-piperidin-1-ylmethyl]-2-phenyl-quinoline-4-carboxylic acid ((S)-1-phenyl-propyl)-amide 713-(2-Oxo-3-oxa-1,8-diaza-spiro[4.5]dec-8-ylmethyl)-2-phenyl-quinoline-4-carboxylic acid ((S)-1-phenyl-propyl)-amide 723-[4-(3,4-Dioxo-2-pyrrolidin-1-yl-cyclobut-1-enyl)-piperazin-1-ylmethyl]-2-phenyl-quinoline-4-carboxylic acid((S)-1-cyclohexyl-ethyl)-amide 733-[4-(-1-Cyanoimino-1-methylamino-methyl)-piperazin-1-ylmethyl]-2-phenyl-quinoline-4-carboxylic acid((S)-1-cyclohexyl-ethyl)amide 743-[4-(4,5-Dihydro-thiazol-2-yl)-piperazin-1-ylmethyl]-2-phenyl-quinoline-4-carboxylic acid ((S)-1-cyclohexyl-ethyl)-amide 753-(4-Methylthiocarbamoyl-piperazin-1-ylmethyl)-2-phenyl-quinoline-4-carboxylic acid ((S)-1-cyclohexyl-ethyl)-amide 763-[4-(1-Cyanoimino-1-pyrrolidin-1-yl-methyl)-piperazin-1-ylmethyl]-2-phenyl-quinoline-4-carboxylic acid((S)-1-cyclohexyl-ethyl)-amide 773-[4-(2-Oxo-imidazolidin-1-yl)-piperidin-1-ylmethyl]-2-phenyl-quinoline-4-carboxylic acid ((S)-1-phenyl-propyl)-amide 783-[4-(1-Methylimino-1-pyrrolidin-1-yl-methyl)-piperazin-1-ylmethyl]-2-phenyl-quinoline-4-carboxylic acid((S)-1-cyclohexyl-ethyl)-amide 793-[1,4′]Bipiperidinyl-1′-ylmethyl-2-phenyl- quinoline-4-carboxylic acid((S)-2-methyl-1-phenyl-propyl)-amide 803-[4-(3-Diethylamino-propanoyl)-piperazin-1-ylmethyl]-2-phenyl-quinoline-4-carboxylic acid((S)-2-methyl-1-phenyl-propyl)-amide 813-[4-(2-Nitro-1-pyrrolidin-1-yl-vinyl)-piperazin-1-ylmethyl]-2-phenyl-quinoline-4-carboxylic acid((S)-1-cyclohexyl-ethyl)-amide 823-(4-Carbamimidoyl-piperazin-1-ylmethyl)-2-phenyl-quinoline-4-carboxylic acid ((S)-1-cyclohexyl-ethyl)-amide 834-{4-[4-((S)-1-Cyclohexyl-ethylcarbamoyl)-2-phenyl-quinolin-3-ylmethyl]-piperazin-1-yl}-4-oxo-butyric acid 843-[4-(1-Methanesulfonylimino-1-pyrrolidin-1-yl-methyl)-piperazin-1-ylmethyl]-2-phenyl-quinoline-4- carboxylic acid((S)-1-cyclohexyl-ethyl)-amide 854-{4-[4-((S)-2-Methyl-1-phenyl-propylcarbamoyl)-2-phenyl-quinolin-3-ylmethyl]-piperazin-1-yl}-4-oxo- butyric acid 862-(1-{4-[4-((S)-2-Methyl-1-phenyl-propylcarbamoyl)-2-phenyl-quinolin-3-ylmethyl]-piperazin-1-yl}- methanoyl)-benzoic acid 872-(1-{4-[4-((S)-1-Cyclohexyl-ethylcarbamoyl)-2-phenyl-quinolin-3-ylmethyl]-piperazin-1-yl}- methanoyl)-benzoic acid 883-[1,4′]Bipiperidinyl-1′-ylmethyl-7-methoxy-2-phenyl--quinoline-4-carboxylic acid ((S)-1-cyclohexyl-ethyl)-amide 893-[1,4′]Bipiperidinyl-1′-ylmethyl-8-chloro-7-hydroxy-2-phenyl-quinoline-4-carboxylic acid ((S)-1-phenyl-propyl)-amide 902-Phenyl-3-(4-sulfamoyl-piperazin-1-ylmethyl)-quinoline-4- carboxylicacid ((S)-1-phenyl-propyl)-amide 913-(4-Dimethylsulfamoyl-piperazin-1-ylmethyl)-2-phenyl-quinoline-4-carboxylic acid ((S)-1-phenyl-propyl)-amide 92{4-[4-((S)-1-Cyclohexyl-ethylcarbamoyl)-2-phenyl-quinolin-3-ylmethyl]-piperazin-1-yl}-acetic acid 932-Phenyl-3-(4-piperazin-1-yl-piperidin-1-ylmethyl)-quinoline-4-carboxylic acid ((S)-2-methyl-1-phenyl-propyl)-amide 943-[1,4′]Bipiperidinyl-1′-ylmethyl-2-phenyl- quinoline-4-carboxylic acid((S)-1-cycloheptyl-ethyl)-amide 953-[1,4′]Bipiperidinyl-1′-ylmethyl-7-hydroxy-2-phenyl-quinoline-4-carboxylic acid ((S)-1-phenyl-propyl)-amide

What is claimed is:
 1. A compound selected from:3-(4-Cyclohexyl-piperazin-1-ylmethyl)-2-phenyl-quinoline-4-carboxylicacid ((S)-1-phenyl-propyl)-amide;2-Phenyl-3-(4-phenyl-piperidin-1-ylmethyl)-quinoline-4-carboxylic acid((S)-1-phenyl-propyl)-amide;3-(4-Benzyl-piperazin-1-ylmethyl)-2-phenyl-quinoline-4-carboxylic acid((S)-1-cyclohexyl-ethyl)-amide;3-(4-Isopropyl-piperazin-1-ylmethyl)-2-phenyl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide;3-(4-Phenethyl-piperazin-1-ylmethyl)-2-phenyl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide;3-[4-(3-Methyl-butyl)-piperazin-1-ylmethyl]-2-phenyl-quinoline-4-carboxylicacid ((S)-1-phenyl-propyl)-amide;3-[4-(3,3-Dimethyl-butyl)-piperazin-1-ylmethyl]-2-phenyl-quinoline-4-carboxylicacid ((S)-1-phenyl-propyl)-amide;3-(4-Isobutyl-piperazin-1-ylmethyl)-2-phenyl-quinoline-4-carboxylic acid((S)-1-phenyl-propyl)-amide;3-(4-Cyclohexylmethyl-piperazin-1-ylmethyl)-2-phenyl-quinoline-4-carboxylicacid ((S)-1-phenyl-propyl)-amide;3-[4-(2-Ethyl-butyl)-piperazin-1-ylmethyl]-2-phenyl-quinoline-4-carboxylicacid ((S)-1-phenyl-propyl)-amide;3-[(Acetyl-methyl-amino)-phenyl-piperidin-1-ylmethyl]-2-phenyl-quinoline-4-carboxylicacid ((S)-1-phenyl-propyl)-amide;3-(4-Oxo-1-phenyl-1,3,8-triaza-spiro[4.5]dec-8-ylmethyl)-2-phenyl-quinoline-4-carboxylicacid ((S)-1-phenyl-propyl)-amide;3-[1,4′]Bipiperidinyl-1′-ylmethyl-2-phenyl-quinoline-4-carboxylic acid((S)-1-cyclohexyl-ethyl)-amide;3-[1,4′]Bipiperidinyl-1′-ylmethyl-2-phenyl-quinoline-4-carboxylic acid((S)-1-phenyl-propyl)-amide;3-{4-[2-(2-Hydroxy-ethoxy)-ethyl]-piperazin-1-ylmethyl}-2-phenyl-quinoline-4-carboxylicacid ((S)-1-phenyl-propyl)-amide;3-[4-(2-Methoxy-ethyl)-piperazin-1-ylmethyl]-2-phenyl-quinoline-4-carboxylicacid ((S)-1-phenyl-propyl)-amide;3-[4-(2-Methoxy-ethyl)-piperazin-1-ylmethyl]-2-phenyl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide;3-(4-Hydroxy-[1,4′]bipiperidinyl-1′-ylmethyl)-2-phenyl-quinoline-4-carboxylicacid ((S)-1-phenyl-propyl)-amide;3-(4-Morpholin-4-yl-piperidin-1-ylmethyl)-2-phenyl-quinoline-4-carboxylicacid ((S)-1-phenyl-propyl)-amide;3-{4-[2-(2-Hydroxy-ethoxy)-ethyl]-piperazin-1-ylmethyl}-2-phenyl-quinoline-4carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide;3-{[(1-Benzyl-piperidin-4-yl)-methyl-amino]-methyl}-2-phenyl-quinoline-4-carboxylicacid ((S)-1-phenyl-propyl)-amide;3-{[(1-Benzyl-piperidin-4-yl)-methyl-amino]-methyl}-2-phenyl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide;3-(4-Acetyl-piperazin-1-ylmethyl)-2-phenyl-quinoline-4-carboxylic acid((S)-1-phenyl-propyl)-amide;2-Phenyl-3-[4-(1-phenyl-methanoyl)-piperazin-1-ylmethyl]-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide;3-[4-(2-Methyl-propanoyl)-piperazin-1-ylmethyl]-2-phenyl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide;2-Phenyl-3-(4-pyrimidin-2-yl-piperazin-1-ylmethyl)-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide;2-Phenyl-3-(4-pyrimidin-2-yl-piperazin-1-ylmethyl)-quinoline-4-carboxylicacid ((S)-1-phenyl-propyl)-amide;3-[4-(2-Hydroxy-ethyl)-piperazin-1-ylmethyl]-2-phenyl-quinoline-4-carboxylicacid ((S)-1-phenyl-propyl)-amide;3-[4-(2-Hydroxy-ethyl)-piperazin-1-ylmethyl]-2-phenyl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide;3-[1,4′]Bipiperidinyl-1′-ylmethyl-2-phenyl-quinoline-4-carboxylic acid((S)-1-phenyl-ethyl)-amide;2-Phenyl-3-[4-(1-phenyl-methanoyl)-piperazin-1-ylmethyl]-quinoline-4-carboxylicacid ((S)-1-phenyl-propyl)-amide;3-[4-(1-Methyl-piperidin-4-yl)-piperazin-1-ylmethyl]-2-phenyl-quinoline-4-carboxylicacid ((S)-1-phenyl-propyl)-amide;3-[4-(1-Methyl-piperidin-4-yl)-piperazin-1-ylmethyl]-2-phenyl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide;2-Phenyl-3-piperazin-1-ylmethyl-quinoline-4-carboxylic acid((S)-1-cyclohexyl-ethyl)-amide;3-{[Bis-(2-diethylamino-ethyl)-amino]-methyl}-2-phenyl-quinoline-4-carboxylicacid ((S)-1-phenyl-propyl)-amide;3-(4-Carbamoyl-piperidin-1-ylmethyl)-2-phenyl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide;3-(4-Ethyl-piperazin-1-ylmethyl)-2-phenyl-quinoline-4-carboxylic acid((S)-1-cyclohexyl-ethyl)-amide;3-[4-(2-Oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-ylmethyl]-2-phenyl-quinoline-4-carboxylicacid ((S)-1-phenyl-propyl)-amide;3-[4-(2-Oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-ylmethyl]-2-phenyl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide;3-{[Methyl-(1-methyl-piperidin-4-yl)-amino]-methyl}-2-phenyl-quinoline-4-carboxylicacid ((S)-1-phenyl-propyl)-amide;3-{[Bis-(2-diethylamino-ethyl)-amino]-methyl}-2-phenyl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide;3-(4-Morpholin-4-yl-piperidin-1-ylmethyl)-2-phenyl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide;3-(4-Hydroxy-[1,4′]bipiperidinyl-1′-ylmethyl)-2-phenyl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide;3-(3-Diethylcarbamoyl-piperidin-1-ylmethyl)-2-phenyl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide;3-(3-Diethylcarbamoyl-piperidin-1-ylmethyl)-2-phenyl-quinoline-4-carboxylicacid ((S)-1-phenyl-propyl)-amide;3-[4-(2-Dimethylamino-ethanoyl)-piperazin-1-ylmethyl]-2-phenyl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide;3-[4-(3-Diethylamino-propanoyl)-piperazin-1-ylmethyl]-2-phenyl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide;3-{4-[2-(4-Methyl-piperazin-1-yl)-ethanoyl]-piperazin-1-ylmethyl}-2-phenyl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide;3-(Hexahydro-pyrrolo[1,2-a]pyrazin-2-ylmethyl)-2-phenyl-quinoline-4-carboxylicacid ((S)-1-phenyl-propyl)-amide;3-[1,4′]Bipiperidinyl-1′-ylmethyl-2-phenyl-quinoline-4-carboxylic acid;3-[4-(3-Morpholin-4-yl-propanoyl)-piperazin-1-ylmethyl]-2-phenyl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide;3-[4-(2-1H-Imidazol-4-yl-ethanoyl)-piperazin-1-ylmethyl]-2-phenyl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide;({4-[4-((S)-1-Cyclohexyl-ethylcarbamoyl)-2-phenyl-quinolin-3-ylmethyl]-piperazin-1-yl}-dimethylamino-methylene)-dimethyl-ammonium;3-Morpholin-4-ylmethyl-2-phenyl-quinoline-4-carboxylic acid((S)-1-cyclohexyl-ethyl)-amide;3-(4-Amino-piperidin-1-ylmethyl)-2-phenyl-quinoline-4-carboxylic acid((S)-1-phenyl-propyl)-amide;2-Phenyl-3-(4-pyridin-2-yl-piperazin-1-ylmethyl)-quinoline-4-carboxylicacid ((S)-1-phenyl-propyl)-amide;3-{[Bis-(2-methoxy-ethyl)-amino]-methyl}-2-phenyl-quinoline-4-carboxylicacid ((S)-1-phenyl-propyl)-amide;3-{[Bis-(2-methoxy-ethyl)-amino]-methyl}-2-phenyl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide;2-Phenyl-3-(4-pyridin-2-yl-piperazin-1-ylmethyl)-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide;3-((3R,5S)-3,5-Dimethyl-piperazin-1-ylmethyl)-2-phenyl-quinoline-4-carboxylicacid ((S)-1-phenyl-propyl)-amide;3-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-ylmethyl)-2-phenyl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide;3-[4-(4-Methyl-piperazin-1-yl)-piperidin-1-ylmethyl]-2-phenylquinoline-4-carboxylicacid ((S)-1-phenyl-propyl)-amide;3-(3-Oxo-2,8-diaza-spiro[4.5]dec-8-ylmethyl)-2-phenyl-quinoline-4-carboxylicacid ((S)-1-phenyl-propyl)-amide;3-(2,4-Dioxo-1,3,8-triaza-spiro[4.5]dec-8-ylmethyl)-2-phenyl-quinoline-4-carboxylicacid ((S)-1-phenyl-propyl)-amide;3-[4-(1-Methyl-piperidin-4-yl)-piperazin-1-ylmethyl]-2-phenyl-quinoline-4-carboxylicacid benzylamide;3-[1,4′]Bipiperidinyl-1′-ylmethyl-8-bromo-7-methoxy-2-phenyl-quinoline-4-carboxylicacid ((S)-1-phenyl-propyl)-amide;3-[1,4′]Bipiperidinyl-1′-ylmethyl-7-methoxy-2-phenyl-quinoline-4-carboxylicacid ((S)-1-phenyl-propyl)-amide;3-(7-Methyl-2,7-diaza-spiro[4.4]non-2-ylmethyl)-2-phenyl-quinoline-4-carboxylicacid ((S)-1-phenyl-propyl)-amide;3-[1,4′]Bipiperidinyl-1′-ylmethyl-2-phenyl-quinoline-4carboxylic acid((S)-1-cyclopentyl-ethyl)-amide;3-[4-(2-Oxo-tetrahydro-pyrimidin-1-yl)-piperidin-1-ylmethyl]-2-phenyl-quinoline-4-carboxylicacid ((S)-1-phenyl-propyl)-amide;3-(2-Oxo-3-oxa-1,8-diaza-spiro[4.5]dec-8-ylmethyl)-2-phenyl-quinoline-4-carboxylicacid ((S)-1-phenyl-propyl)-amide;3-[4-(3,4-Dioxo-2-pyrrolidin-1-yl-cyclobut-1-enyl)-piperazin-1-ylmethyl]-2-phenyl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide;3-[4-(-1-Cyanoimino-1-methylamino-methyl)-piperazin-1-ylmethyl]-2-phenyl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)amide;3-[4-(4,5-Dihydro-thiazol-2-yl)-piperazin-1-ylmethyl]-2-phenyl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide;3-(4-Methylthiocarbamoyl-piperazin-1-ylmethyl)-2-phenyl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide;3-[4-(1-Cyanoimino-1-pyrrolidin-1-yl-methyl)-piperazin-1-ylmethyl]-2-phenyl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide;3-[4-(2-Oxo-imidazolidin-1-yl)-piperidin-1-ylmethyl]-2-phenyl-quinoline-4-carboxylicacid ((S)-1-phenyl-propyl)-amide;3-[4-(1-Methylimino-1-pyrrolidin-1-yl-methyl)-piperazin-1-ylmethyl]-2-phenyl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide;3-[1,4′]Bipiperidinyl-1′-ylmethyl-2-phenyl-quinoline-4-carboxylic acid((S)-2-methyl-1-phenyl-propyl)-amide;3-[4-(3-Diethylamino-propanoyl)-piperazin-1-ylmethyl]-2-phenyl-quinoline-4-carboxylicacid ((S)-2-methyl-1-phenyl-propyl)-amide;3-[4-(2-Nitro-1-pyrrolidin-1-yl-vinyl)-piperazin-1-ylmethyl]-2-phenyl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide;3-(4-Carbamimidoyl-piperazin-1-ylmethyl)-2-phenyl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide;4-{4-[4-((S)-1-Cyclohexyl-ethylcarbamoyl)-2-phenyl-quinolin-3-ylmethyl]-piperazin-1-yl}-4-oxo-butyricacid;3-[4-(1-Methanesulfonylimino-1-pyrrolidin-1-yl-methyl)-piperazin-1-ylmethyl]-2-phenyl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide;4-{4-[4-((S)-2-Methyl-1-phenyl-propylcarbamoyl)-2-phenyl-quinolin-3-ylmethyl]-piperazin-1-yl}-4-oxo-butyricacid;2-(1-{4-[4-((S)-2-Methyl-1-phenyl-propylcarbamoyl)-2-phenyl-quinolin-3-ylmethyl]-piperazin-1-yl}-methanoyl)-benzoicacid;2-(1-{4-[4-((S)-1-Cyclohexyl-ethylcarbamoyl)-2-phenyl-quinolin-3-ylmethyl]-piperazin-1-yl}-methanoyl)-benzoicacid;3-[1,4′]Bipiperidinyl-1′-ylmethyl-7-methoxy-2-phenyl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide;3-[1,4′]Bipiperidinyl-1′-ylmethyl-8-chloro-7-hydroxy-2-phenyl-quinoline-4-carboxylicacid ((S)-1-phenyl-propyl)-amide;2-Phenyl-3-(4-sulfamoyl-piperazin-1-ylmethyl)-quinoline-4-carboxylicacid ((S)-1-phenyl-propyl)-amide;3-(4-Dimethylsulfamoyl-piperazin-1-ylmethyl)-2-phenyl-quinoline-4-carboxylicacid ((S)-1-phenyl-propyl)-amide;{4-[4-((S)-1-Cyclohexyl-ethylcarbamoyl)-2-phenyl-quinolin-3-ylmethyl]-piperazin-1-yl}-aceticacid;2-Phenyl-3-(4-piperazin-1-yl-piperidin-1-ylmethyl)-quinoline-4-carboxylicacid ((S)-2-methyl-1-phenyl-propyl)-amide;3-[1,4′]Bipiperidinyl-1′-ylmethyl-2-phenylquinoline-4-carboxylic acid((S)-1-cycloheptyl-ethyl)-amide; and3-[1,4′]Bipiperidinyl-1′-ylmethyl-7-hydroxy-2-phenyl-quinoline-4-carboxylicacid ((S)-1-phenyl-propyl)-amide.
 2. A compound selected from:3-{4-[2-(2-Hydroxy-ethoxy)-ethyl]-piperazin-1-ylmethyl}-2-phenyl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide;3-[4-(2-Hydroxy-ethyl)-piperazin-1-ylmethyl]-2-phenyl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide;3-[4-(1-Methyl-piperidin-4-yl)-piperazin-1-ylmethyl]-2-phenyl-quinoline-4-carboxylicacid ((S)-1-phenyl-propyl)-amide;3-[4-(1-Methyl-piperidin-4-yl)-piperazin-1-ylmethyl]-2-phenyl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide;2-Phenyl-3-piperazin-1-ylmethyl-quinoline-4-carboxylic acid((S)-1-cyclohexyl-ethyl)-amide;3-[4-(2-Dimethylamino-ethanoyl)-piperazin-1-ylmethyl]-2-phenyl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide;3-[4-(3-Diethylamino-propanoyl)-piperazin-1-ylmethyl]-2-phenyl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide;3-{4-[2-(4-Methyl-piperazin-1-yl)-ethanoyl]-piperazin-1-ylmethyl}-2-phenyl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide;({4-[4-((S)-1-Cyclohexyl-ethylcarbamoyl)-2-phenyl-quinolin-3-ylmethyl]-piperazin-1-yl}-dimethylamino-methylene)-dimethyl-ammonium;3-(4-Amino-piperidin-1-ylmethyl)-2-phenyl-quinoline-4-carboxylic acid((S)-1-phenyl-propyl)-amide;3-[4-(4-Methyl-piperazin-1-yl)-piperidin-1-ylmethyl]-2-phenyl-quinoline-4-carboxylicacid ((S)-1-phenyl-propyl)-amide;3-[1,4′]Bipiperidinyl-1′-ylmethyl-7-methoxy-2-phenyl-quinoline-4-carboxylicacid ((S)-1-phenyl-propyl)-amide;3-[4-(1-Methylimino-1-pyrrolidin-1-yl-methyl)-piperazin-1-ylmethyl]-2-phenyl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide;3-[1,4′]Bipiperidinyl-1′-ylmethyl-2-phenyl-quinoline-4-carboxylic acid((S)-2-methyl-1-phenyl-propyl)-amide;3-[4-(3-Diethylamino-propanoyl)-piperazin-1-ylmethyl]-2-phenyl-quinoline-4-carboxylicacid ((S)-2-methyl-1-phenyl-propyl)-amide;3-[4-(2-Nitro-1-pyrrolidin-1-yl-vinyl)-piperazin-1-ylmethyl]-2-phenyl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide; and3-[1,4′]Bipiperidinyl-1′-ylmethyl-7-hydroxy-2-phenyl-quinoline-4-carboxylicacid ((S)-1-phenyl-propyl)-amide.
 3. A pharmaceutical compositioncomprising a compound according to claim 1 or a pharmaceuticallyacceptable salt or solvate thereof, and a pharmaceutically acceptablecarrier.
 4. A pharmaceutical composition comprising a compound accordingto claim 2 or a pharmaceutically acceptable salt or solvate thereof, anda pharmaceutically acceptable carrier.
 5. A compound which is3-[1,4′]Bipiperidinyl-1′-ylmethyl-2-phenyl-quinoline-4-carboxylic acid((S)-1-cyclohexyl-ethyl)-amide dihydrochloride.
 6. A pharmaceuticalcomposition comprising a compound according to claim 5 or apharmaceutically acceptable solvate thereof, and a pharmaceuticallyacceptable carrier.